Prognostic significance of tumor immune microenvironment and immunotherapy: Novel insights and future perspectives in gastric cancer
详细信息    查看全文 | 推荐本文 |
  • 英文篇名:Prognostic significance of tumor immune microenvironment and immunotherapy: Novel insights and future perspectives in gastric cancer
  • 作者:Daniela ; Cornelia ; Laz?r ; Mihaela ; Flavia ; Avram ; Ioan ; Romo?an ; M?rioara ; Cornianu ; Sorina ; T?ban ; Adrian ; Goldi?
  • 英文作者:Daniela Cornelia Laz?r;Mihaela Flavia Avram;Ioan Romo?an;M?rioara Cornianu;Sorina T?ban;Adrian Goldi?;Department of Internal Medicine I, University Medical Clinic, University of Medicine and Pharmacy "Victor Babe?";Department of Surgery X, 1st Surgery Clinic, University of Medicine and Pharmacy "Victor Babe?";Department of Pathology, University of Medicine and Pharmacy "Victor Babe?";Department of Gastroenterology and Hepatology, University of Medicine and Pharmacy "Victor Babe?";
  • 英文关键词:Immunotherapy;;Prognostic significance;;Tumor immune microenvironment;;Immune checkpoint inhibitors;;Gastric cancer
  • 中文刊名:ZXXY
  • 英文刊名:世界胃肠病学杂志(英文版)
  • 机构:Department of Internal Medicine I, University Medical Clinic, University of Medicine and Pharmacy "Victor Babe?";Department of Surgery X, 1st Surgery Clinic, University of Medicine and Pharmacy "Victor Babe?";Department of Pathology, University of Medicine and Pharmacy "Victor Babe?";Department of Gastroenterology and Hepatology, University of Medicine and Pharmacy "Victor Babe?";
  • 出版日期:2018-08-28
  • 出版单位:World Journal of Gastroenterology
  • 年:2018
  • 期:v.24
  • 语种:英文;
  • 页:ZXXY201832002
  • 页数:34
  • CN:32
  • 分类号:20-53
摘要
Despite a decrease in gastric cancer incidence, the development of novel biologic agents and combined therapeutic strategies, the prognosis of gastric cancer remains poor. Recently, the introduction of modern immunotherapy, especially using immune checkpoint inhibitors, led to an improved prognosis in many cancers. The use of immunotherapy was also associated with manageable adverse event profiles and promising results in the treatment of patients with gastric cancer, especially in heavily pretreated patients. These data have led to an accelerated approval of some checkpoint inhibitors in this setting. Understanding the complex relationship between the host immune microenvironment and tumor and the immune escape phenomenon leading to cancer occurrence and progression will subsequently lead to the identification of prognostic immune markers. Furthermore, this understanding will result in the discovery of both new mechanisms for blocking tumor immunosuppressive signals and pathways to stimulate the local immune response by targeting and modulating different subsets of immune cells. Due to the molecular heterogeneity of gastric cancers associated with differentclinico-biologic parameters, immune markers expression and prognosis, novel immunotherapy algorithms should be personalized and addressed to selected subsets of gastric tumors, which have been proven to elicit the best clinical responses. Future perspectives in the treatment of gastric cancer include tailored dual immunotherapies or a combination of immunotherapy with other targeted agents with synergistic antitumor effects.
        Despite a decrease in gastric cancer incidence, the development of novel biologic agents and combined therapeutic strategies, the prognosis of gastric cancer remains poor. Recently, the introduction of modern immunotherapy, especially using immune checkpoint inhibitors, led to an improved prognosis in many cancers. The use of immunotherapy was also associated with manageable adverse event profiles and promising results in the treatment of patients with gastric cancer, especially in heavily pretreated patients. These data have led to an accelerated approval of some checkpoint inhibitors in this setting. Understanding the complex relationship between the host immune microenvironment and tumor and the immune escape phenomenon leading to cancer occurrence and progression will subsequently lead to the identification of prognostic immune markers. Furthermore, this understanding will result in the discovery of both new mechanisms for blocking tumor immunosuppressive signals and pathways to stimulate the local immune response by targeting and modulating different subsets of immune cells. Due to the molecular heterogeneity of gastric cancers associated with differentclinico-biologic parameters, immune markers expression and prognosis, novel immunotherapy algorithms should be personalized and addressed to selected subsets of gastric tumors, which have been proven to elicit the best clinical responses. Future perspectives in the treatment of gastric cancer include tailored dual immunotherapies or a combination of immunotherapy with other targeted agents with synergistic antitumor effects.
引文
1 Ferlay J,Soerjomataram I,Ervik M,Dikshit R,Eser S,Mathers C,Rebelo M,Parkin DM,Forman D,Bray,F.Estimated incidence,mortality and prevalence worldwide in 2012.2013.[Internet].Lyon,France:International Agency for Research on Cancer.Accessed May4,2018 Available from:URL:http://globocan.iarc.fr/Default.aspx
    2 Waddell T,Verheij M,Allum W,Cunningham D,Cervantes A,Arnold D;European Society for Medical Oncology(ESMO);European Society of Surgical Oncology(ESSO);European Society of Radiotherapy and Oncology(ESTRO).Gastric cancer:ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis,treatment and follow-up.Ann Oncol 2013;24 Suppl 6:vi57-vi63[PMID:24078663 DOI:10.1093/annonc/mdt344]
    3 Okines AF,Norman AR,Mc Cloud P,Kang YK,Cunningham D.Meta-analysis of the REAL-2 and ML17032 trials:evaluating capecitabine-based combination chemotherapy and infused5-fluorouracil-based combination chemotherapy for the treatment of advanced oesophago-gastric cancer.Ann Oncol 2009;20:1529-1534[PMID:19474114 DOI:10.1093/annonc/mdp047]
    4 Bang YJ,Van Cutsem E,Feyereislova A,Chung HC,Shen L,Sawaki A,Lordick F,Ohtsu A,Omuro Y,Satoh T,Aprile G,Kulikov E,Hill J,Lehle M,Rüschoff J,Kang YK;To GA Trial Investigators.Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer(To GA):a phase 3,open-label,randomised controlled trial.Lancet 2010;376:687-697[PMID:20728210 DOI:10.1016/S0140-6736(10)61121-X]
    5 Fuchs CS,Tomasek J,Yong CJ,Dumitru F,Passalacqua R,Goswami C,Safran H,Dos Santos LV,Aprile G,Ferry DR,Melichar B,Tehfe M,Topuzov E,Zalcberg JR,Chau I,Campbell W,Sivanandan C,Pikiel J,Koshiji M,Hsu Y,Liepa AM,Gao L,Schwartz JD,Tabernero J;REGARD Trial Investigators.Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma(REGARD):an international,randomised,multicentre,placebo-controlled,phase 3 trial.Lancet 2014;383:31-39[PMID:24094768 DOI:10.1016/S0140-6736(13)61719-5]
    6 Wilke H,Muro K,Van Cutsem E,Oh SC,Bodoky G,Shimada Y,Hironaka S,Sugimoto N,Lipatov O,Kim TY,Cunningham D,Rougier P,Komatsu Y,Ajani J,Emig M,Carlesi R,Ferry D,Chandrawansa K,Schwartz JD,Ohtsu A;RAINBOW Study Group.Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastrooesophageal junction adenocarcinoma(RAINBOW):a double-blind,randomised phase 3 trial.Lancet Oncol 2014;15:1224-1235[PMID:25240821 DOI:10.1016/S1470-2045(14)70420-6]
    7 Hodi FS,O’Day SJ,Mc Dermott DF,Weber RW,Sosman JA,Haanen JB,Gonzalez R,Robert C,Schadendorf D,Hassel JC,Akerley W,van den Eertwegh AJ,Lutzky J,Lorigan P,Vaubel JM,Linette GP,Hogg D,Ottensmeier CH,LebbéC,Peschel C,Quirt I,Clark JI,Wolchok JD,Weber JS,Tian J,Yellin MJ,Nichol GM,Hoos A,Urba WJ.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med 2010;363:711-723[PMID:20525992 DOI:10.1056/NEJMoa1003466]
    8 Robert C,Thomas L,Bondarenko I,O’Day S,Weber J,Garbe C,Lebbe C,Baurain JF,Testori A,Grob JJ,Davidson N,Richards J,Maio M,Hauschild A,Miller WH Jr,Gascon P,Lotem M,Harmankaya K,Ibrahim R,Francis S,Chen TT,Humphrey R,Hoos A,Wolchok JD.Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.N Engl J Med 2011;364:2517-2526[PMID:21639810 DOI:10.1056/NEJMoa1104621]
    9 Lyons TG,Ku GY.Systemic therapy for esophagogastric cancer:immune checkpoint inhibition.Chin Clin Oncol 2017;6:53[PMID:29129093 DOI:10.21037/cco.2017.09.03]
    10 Lauwers GY,Carneiro F,Graham DY.Gastric carcinoma.In:Bowman FT,Carneiro F,Hruban RH,eds.Classification of Tumours of the Digestive System.Lyon:IARC,2010
    11 Lauren P.The two histological main types of gastric carcinoma:diffuse and so-called intestinal-type carcinoma.An attempt at a histoclinical classification.Acta Pathol Microbiol Scand 1965;64:31-49[PMID:14320675 DOI:10.1111/apm.1965.64.1.31]
    12 Garattini SK,Basile D,Cattaneo M,Fanotto V,Ongaro E,Bonotto M,Negri FV,Berenato R,Ermacora P,Cardellino GG,Giovannoni M,Pella N,Scartozzi M,Antonuzzo L,Silvestris N,Fasola G,Aprile G.Molecular classifications of gastric cancers:Novel insights and possible future applications.World J Gastrointest Oncol 2017;9:194-208[PMID:28567184 DOI:10.4251/wjgo.v9.i5.194]
    13 Lei Z,Tan IB,Das K,Deng N,Zouridis H,Pattison S,Chua C,Feng Z,Guan YK,Ooi CH,Ivanova T,Zhang S,Lee M,Wu J,Ngo A,Manesh S,Tan E,Teh BT,So JB,Goh LK,Boussioutas A,Lim TK,Flotow H,Tan P,Rozen SG.Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil.Gastroenterology 2013;145:554-565[PMID:23684942 DOI:10.1053/j.gastro.2013.05.010]
    14 Lim B,Kim JH,Kim M,Kim SY.Genomic and epigenomic heterogeneity in molecular subtypes of gastric cancer.World J Gastroenterol 2016;22:1190-1201[PMID:26811657 DOI:10.3748/wjg.v22.i3.1190]
    15 Aprile G,Giampieri R,Bonotto M,Bittoni A,Ongaro E,Cardellino GG,Graziano F,Giuliani F,Fasola G,Cascinu S,Scartozzi M.The challenge of targeted therapies for gastric cancer patients:the beginning of a long journey.Expert Opin Investig Drugs 2014;23:925-942[PMID:24806575 DOI:10.1517/13543784.2014.912631]
    16 Chen T,Xu XY,Zhou PH.Emerging molecular classifications and therapeutic implications for gastric cancer.Chin J Cancer 2016;35:49[PMID:27233623 DOI:10.1186/s40880-016-0111-5]
    17 Tan P,Yeoh KG.Genetics and Molecular Pathogenesis of Gastric Adenocarcinoma.Gastroenterology 2015;149:1153-1162.e3[PMID:26073375 DOI:10.1053/j.gastro.2015.05.059]
    18 Pedrazzani C,Corso G,Velho S,Leite M,Pascale V,Bettarini F,Marrelli D,Seruca R,Roviello F.Evidence of tumor microsatellite instability in gastric cancer with familial aggregation.Fam Cancer 2009;8:215-220[PMID:19152022 DOI:10.1007/s10689-008-9231-7]
    19 Velho S,Fernandes MS,Leite M,Figueiredo C,Seruca R.Causes and consequences of microsatellite instability in gastric carcinogenesis.World J Gastroenterol 2014;20:16433-16442[PMID:25469011 DOI:10.3748/wjg.v20.i44.16433]
    20 Chung DC,Rustgi AK.DNA mismatch repair and cancer.Gastroenterology 1995;109:1685-1699[PMID:7557155 DOI:10.1016/0016-5085(95)90660-6]
    21 Zhu L,Li Z,Wang Y,Zhang C,Liu Y,Qu X.Microsatellite instability and survival in gastric cancer:A systematic review and meta-analysis.Mol Clin Oncol 2015;3:699-705[PMID:26137290DOI:10.3892/mco.2015.506]
    22 Topalian SL,Hodi FS,Brahmer JR,Gettinger SN,Smith DC,Mc Dermott DF,Powderly JD,Carvajal RD,Sosman JA,Atkins MB,Leming PD,Spigel DR,Antonia SJ,Horn L,Drake CG,Pardoll DM,Chen L,Sharfman WH,Anders RA,Taube JM,Mc Miller TL,Xu H,Korman AJ,Jure-Kunkel M,Agrawal S,Mc Donald D,Kollia GD,Gupta A,Wigginton JM,Sznol M.Safety,activity,and immune correlates of anti-PD-1 antibody in cancer.N Engl J Med 2012;366:2443-2454[PMID:22658127 DOI:10.1056/NEJMoa1200690]
    23 Le DT,Uram JN,Wang H,Bartlett BR,Kemberling H,Eyring AD,Skora AD,Luber BS,Azad NS,Laheru D,Biedrzycki B,Donehower RC,Zaheer A,Fisher GA,Crocenzi TS,Lee JJ,Duffy SM,Goldberg RM,de la Chapelle A,Koshiji M,Bhaijee F,Huebner T,Hruban RH,Wood LD,Cuka N,Pardoll DM,Papadopoulos N,Kinzler KW,Zhou S,Cornish TC,Taube JM,Anders RA,Eshleman JR,Vogelstein B,Diaz LA Jr.PD-1 Blockade in Tumors with MismatchRepair Deficiency.N Engl J Med 2015;372:2509-2520[PMID:26028255 DOI:10.1056/NEJMoa1500596]
    24 Schwitalle Y,Kloor M,Eiermann S,Linnebacher M,Kienle P,Knaebel HP,Tariverdian M,Benner A,von Knebel Doeberitz M.Immune response against frameshift-induced neopeptides in HNPCC patients and healthy HNPCC mutation carriers.Gastroenterology 2008;134:988-997[PMID:18395080 DOI:10.1053/j.gastro.2008.01.015]
    25 Muro K,Chung HC,Shankaran V,Geva R,Catenacci D,Gupta S,Eder JP,Golan T,Le DT,Burtness B,Mc Ree AJ,Lin CC,Pathiraja K,Lunceford J,Emancipator K,Juco J,Koshiji M,Bang YJ.Pembrolizumab for patients with PD-L1-positive advanced gastric cancer(KEYNOTE-012):a multicentre,open-label,phase 1b trial.Lancet Oncol 2016;17:717-726[PMID:27157491 DOI:10.1016/S1470-2045(16)00175-3]
    26 Bristol-Myers Squibb.A Study of Nivolumab and Nivolumab Plus Ipilimumab in Recurrent and Metastatic Colon Cancer(Check Mate142).[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:https://clinicaltrials.gov/ct2/show/NCT02060188 Clinical Trials.gov Identifier:NCT02060188
    27 Buckowitz A,Knaebel HP,Benner A,Bl?ker H,Gebert J,Kienle P,von Knebel Doeberitz M,Kloor M.Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases.Br J Cancer 2005;92:1746-1753[PMID:15856045 DOI:10.1038/sj.bjc.6602534]
    28 Cancer Genome Atlas Research Network.Comprehensive molecular characterization of gastric adenocarcinoma.Nature 2014;513:202-209[PMID:25079317 DOI:10.1038/nature13480]
    29 Murphy G,Pfeiffer R,Camargo MC,Rabkin CS.Meta-analysis shows that prevalence of Epstein-Barr virus-positive gastric cancer differs based on sex and anatomic location.Gastroenterology 2009;137:824-833[PMID:19445939 DOI:10.1053/j.gastro.2009.05.001]
    30 Camargo MC,Murphy G,Koriyama C,Pfeiffer RM,Kim WH,Herrera-Goepfert R,Corvalan AH,Carrascal E,Abdirad A,Anwar M,Hao Z,Kattoor J,Yoshiwara-Wakabayashi E,Eizuru Y,Rabkin CS,Akiba S.Determinants of Epstein-Barr virus-positive gastric cancer:an international pooled analysis.Br J Cancer 2011;105:38-43[PMID:21654677 DOI:10.1038/bjc.2011.215]
    31 Kim SY,Park C,Kim HJ,Park J,Hwang J,Kim JI,Choi MG,Kim S,Kim KM,Kang MS.Deregulation of immune response genes in patients with Epstein-Barr virus-associated gastric cancer and outcomes.Gastroenterology 2015;148:137-147.e9[PMID:25254613 DOI:10.1053/j.gastro.2014.09.020]
    32 Derks S,Liao X,Chiaravalli AM,Xu X,Camargo MC,Solcia E,Sessa F,Fleitas T,Freeman GJ,Rodig SJ,Rabkin CS,Bass AJ.Abundant PD-L1 expression in Epstein-Barr Virus-infected gastric cancers.Oncotarget 2016;7:32925-32932[PMID:27147580 DOI:10.18632/oncotarget.9076]
    33 Cristescu R,Lee J,Nebozhyn M,Kim KM,Ting JC,Wong SS,Liu J,Yue YG,Wang J,Yu K,Ye XS,Do IG,Liu S,Gong L,Fu J,Jin JG,Choi MG,Sohn TS,Lee JH,Bae JM,Kim ST,Park SH,Sohn I,Jung SH,Tan P,Chen R,Hardwick J,Kang WK,Ayers M,Hongyue D,Reinhard C,Loboda A,Kim S,Aggarwal A.Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes.Nat Med 2015;21:449-456[PMID:25894828 DOI:10.1038/nm.3850]
    34 Yingyan Y.A new molecular classification of gastric cancer proposed by Asian Cancer Research Group(ACRG).Transl Gastrointest Cancer 2016;5:55-57[DOI:10.3978/j.issn.2224-4778.2015.12.01]
    35 Burnet M.Cancer;a biological approach.I.The processes of control.Br Med J 1957;1:779-786[PMID:13404306 DOI:10.1136/bmj.1.5022.779]
    36 Matsueda S,Graham DY.Immunotherapy in gastric cancer.World J Gastroenterol 2014;20:1657-1666[PMID:24587645 DOI:10.3748/wjg.v20.i7.1657]
    37 Ferrara N,Gerber HP,Le Couter J.The biology of VEGF and its receptors.Nat Med 2003;9:669-676[PMID:12778165 DOI:10.1038/nm0603-669]
    38 Kandulski A,Malfertheiner P,Wex T.Role of regulatory T-cells in H.pylori-induced gastritis and gastric cancer.Anticancer Res 2010;30:1093-1103[PMID:20530414]
    39 Haraguchi N,Inoue H,Tanaka F,Mimori K,Utsunomiya T,Sasaki A,Mori M.Cancer stem cells in human gastrointestinal cancers.Hum Cell 2006;19:24-29[PMID:16643604 DOI:10.1111/j.1749-0774.2005.00004.x]
    40 Houghton J,Wang TC.Helicobacter pylori and gastric cancer:a new paradigm for inflammation-associated epithelial cancers.Gastroenterology 2005;128:1567-1578[PMID:15887152 DOI:10.1053/j.gastro.2005.03.037]
    41 Lin R,Ma H,Ding Z,Shi W,Qian W,Song J,Hou X.Bone marrowderived mesenchymal stem cells favor the immunosuppressive Tcells skewing in a Helicobacter pylori model of gastric cancer.Stem Cells Dev 2013;22:2836-2848[PMID:23777268 DOI:10.1089/scd.2013.0166]
    42 Procaccio L,Schirripa M,Fassan M,Vecchione L,Bergamo F,Prete AA,Intini R,Manai C,Dadduzio V,Boscolo A,Zagonel V,Lonardi S.Immunotherapy in Gastrointestinal Cancers.Biomed Res Int 2017;2017:4346576[PMID:28758114 DOI:10.1155/2017/4346576]
    43 Topalian SL,Drake CG,Pardoll DM.Targeting the PD-1/B7-H1(PD-L1)pathway to activate anti-tumor immunity.Curr Opin Immunol 2012;24:207-212[PMID:22236695 DOI:10.1016/j.coi.2011.12.009]
    44 Blank C,Gajewski TF,Mackensen A.Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion:implications for tumor immunotherapy.Cancer Immunol Immunother 2005;54:307-314[PMID:15599732 DOI:10.1007/s00262-004-0593-x]
    45 Balch CM,Riley LB,Bae YJ,Salmeron MA,Platsoucas CD,von Eschenbach A,Itoh K.Patterns of human tumor-infiltrating lymphocytes in 120 human cancers.Arch Surg 1990;125:200-205[PMID:1689143 DOI:10.1001/archsurg.1990.01410140078012]
    46 Zheng X,Song X,Shao Y,Xu B,Chen L,Zhou Q,Hu W,Zhang D,Wu C,Tao M,Zhu Y,Jiang J.Prognostic role of tumor-infiltrating lymphocytes in gastric cancer:a meta-analysis.Oncotarget 2017;8:57386-57398[PMID:28915679 DOI:10.18632/oncotarget.18065]
    47 Chen DS,Mellman I.Oncology meets immunology:the cancerimmunity cycle.Immunity 2013;39:1-10[PMID:23890059 DOI:10.1016/j.immuni.2013.07.012]
    48 Kang BW,Kim JG,Lee IH,Bae HI,Seo AN.Clinical significance of tumor-infiltrating lymphocytes for gastric cancer in the era of immunology.World J Gastrointest Oncol 2017;9:293-299[PMID:28808502 DOI:10.4251/wjgo.v9.i7.293]
    49 Schreiber RD,Old LJ,Smyth MJ.Cancer immunoediting:integrating immunity’s roles in cancer suppression and promotion.Science 2011;331:1565-1570[PMID:21436444 DOI:10.1126/science.1203486]
    50 Kang BW,Seo AN,Yoon S,Bae HI,Jeon SW,Kwon OK,Chung HY,Yu W,Kang H,Kim JG.Prognostic value of tumor-infiltrating lymphocytes in Epstein-Barr virus-associated gastric cancer.Ann Oncol 2016;27:494-501[PMID:26673353 DOI:10.1093/annonc/mdv610]
    51 Ishigami S,Natsugoe S,Tokuda K,Nakajo A,Che X,Iwashige H,Aridome K,Hokita S,Aikou T.Prognostic value of intratumoral natural killer cells in gastric carcinoma.Cancer 2000;88:577-583[PMID:10649250 DOI:10.1002/(SICI)1097-0142(20000201)88:3<577::AID-CNCR13>3.0.CO;2-V]
    52 Dirican A,Ekinci N,Avci A,Akyol M,Alacacioglu A,Kucukzeybek Y,Somali I,Erten C,Demir L,Can A,BayogluⅣ,Koyuncu B,Ulger E,Tarhan MO.The effects of hematological parameters and tumor-infiltrating lymphocytes on prognosis in patients with gastric cancer.Cancer Biomark 2013;13:11-20[PMID:23736017 DOI:10.3233/CBM-130331]
    53 Dai C,Geng R,Wang C,Wong A,Qing M,Hu J,Sun Y,Lo AW,Li J.Concordance of immune checkpoints within tumor immune contexture and their prognostic significance in gastric cancer.Mol Oncol 2016;10:1551-1558[PMID:27720576 DOI:10.1016/j.molonc.2016.09.004]
    54 Haas M,Dimmler A,Hohenberger W,Grabenbauer GG,Niedobitek G,Distel LV.Stromal regulatory T-cells are associated with a favourable prognosis in gastric cancer of the cardia.BMC Gastroenterol 2009;9:65[PMID:19732435 DOI:10.1186/1471-230X-9-65]
    55 Kim KJ,Lee KS,Cho HJ,Kim YH,Yang HK,Kim WH,Kang GH.Prognostic implications of tumor-infiltrating Fox P3+regulatory Tcells and CD8+cytotoxic T cells in microsatellite-unstable gastric cancers.Hum Pathol 2014;45:285-293[PMID:24331841 DOI:10.1016/j.humpath.2013.09.004]
    56 Chiaravalli AM,Feltri M,Bertolini V,Bagnoli E,Furlan D,Cerutti R,Novario R,Capella C.Intratumour T cells,their activation status and survival in gastric carcinomas characterised for microsatellite instability and Epstein-Barr virus infection.Virchows Arch 2006;448:344-353[PMID:16261379 DOI:10.1007/s00428-005-0066-4]
    57 Liu K,Yang K,Wu B,Chen H,Chen X,Chen X,Jiang L,Ye F,He D,Lu Z,Xue L,Zhang W,Li Q,Zhou Z,Mo X,Hu J.TumorInfiltrating Immune Cells Are Associated With Prognosis of Gastric Cancer.Medicine(Baltimore)2015;94:e1631[PMID:26426650DOI:10.1097/MD.0000000000001631]
    58 Thompson ED,Zahurak M,Murphy A,Cornish T,Cuka N,Abdelfatah E,Yang S,Duncan M,Ahuja N,Taube JM,Anders RA,Kelly RJ.Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma.Gut 2017;66:794-801[PMID:26801886 DOI:10.1136/gutjnl-2015-310839]
    59 Zhou S,Shen Z,Wang Y,Ma H,Xu S,Qin J,Chen L,Tao H,Zhen Z,Chen G,Zhang Z,Li R,Xiao H,Zhong C,Yang Y,Liang C.CCR7 expression and intratumoral FOXP3+regulatory T cells are correlated with overall survival and lymph node metastasis in gastric cancer.PLo S One 2013;8:e74430[PMID:24040244 DOI:10.1371/journal.pone.0074430]
    60 Wang B,Xu D,Yu X,Ding T,Rao H,Zhan Y,Zheng L,Li L.Association of intra-tumoral infiltrating macrophages and regulatory T cells is an independent prognostic factor in gastric cancer after radical resection.Ann Surg Oncol 2011;18:2585-2593[PMID:21347781 DOI:10.1245/s10434-011-1609-3]
    61 Perrone G,Ruffini PA,Catalano V,Spino C,Santini D,Muretto P,Spoto C,Zingaretti C,Sisti V,Alessandroni P,Giordani P,Cicetti A,D’Emidio S,Morini S,Ruzzo A,Magnani M,Tonini G,Rabitti C,Graziano F.Intratumoural FOXP3-positive regulatory T cells are associated with adverse prognosis in radically resected gastric cancer.Eur J Cancer 2008;44:1875-1882[PMID:18617393 DOI:10.1016/j.ejca.2008.05.017]
    62 Kim KJ,Wen XY,Yang HK,Kim WH,Kang GH.Prognostic Implication of M2 Macrophages Are Determined by the Proportional Balance of Tumor Associated Macrophages and Tumor Infiltrating Lymphocytes in Microsatellite-Unstable Gastric Carcinoma.PLo SOne 2015;10:e0144192[PMID:26714314 DOI:10.1371/journal.pone.0144192]
    63 Hu M,Li K,Maskey N,Xu Z,Peng C,Wang B,Li Y,Yang G.Decreased intratumoral Foxp3 Tregs and increased dendritic cell density by neoadjuvant chemotherapy associated with favorable prognosis in advanced gastric cancer.Int J Clin Exp Pathol 2014;7:4685-4694[PMID:25197340]
    64 Mizukami Y,Kono K,Kawaguchi Y,Akaike H,Kamimura K,Sugai H,Fujii H.Localisation pattern of Foxp3+regulatory T cells is associated with clinical behaviour in gastric cancer.Br J Cancer2008;98:148-153[PMID:18087278 DOI:10.1038/sj.bjc.6604149]
    65 Shen Z,Zhou S,Wang Y,Li RL,Zhong C,Liang C,Sun Y.Higher intratumoral infiltrated Foxp3+Treg numbers and Foxp3+/CD8+ratio are associated with adverse prognosis in resectable gastric cancer.J Cancer Res Clin Oncol 2010;136:1585-1595[PMID:20221835DOI:10.1007/s00432-010-0816-9]
    66 Liu T,Peng L,Yu P,Zhao Y,Shi Y,Mao X,Chen W,Cheng P,Wang T,Chen N,Zhang J,Liu X,Li N,Guo G,Tong W,Zhuang Y,Zou Q.Increased circulating Th22 and Th17 cells are associated with tumor progression and patient survival in human gastric cancer.J Clin Immunol 2012;32:1332-1339[PMID:22760549 DOI:10.1007/s10875-012-9718-8]
    67 Ubukata H,Motohashi G,Tabuchi T,Nagata H,Konishi S,Tabuchi T.Evaluations of interferon-γ/interleukin-4 ratio and neutrophil/lymphocyte ratio as prognostic indicators in gastric cancer patients.J Surg Oncol 2010;102:742-747[PMID:20872813 DOI:10.1002/jso.21725]
    68 Lee HE,Chae SW,Lee YJ,Kim MA,Lee HS,Lee BL,Kim WH.Prognostic implications of type and density of tumour-infiltrating lymphocytes in gastric cancer.Br J Cancer 2008;99:1704-1711[PMID:18941457 DOI:10.1038/sj.bjc.6604738]
    69 Ishigami S,Natsugoe S,Tokuda K,Nakajo A,Xiangming C,Iwashige H,Aridome K,Hokita S,Aikou T.Clinical impact of intratumoral natural killer cell and dendritic cell infiltration in gastric cancer.Cancer Lett 2000;159:103-108[PMID:10974412 DOI:10.1016/S0304-3835(00)00542-5]
    70 Mimura K,Kamiya T,Shiraishi K,Kua LF,Shabbir A,So J,Yong WP,Suzuki Y,Yoshimoto Y,Nakano T,Fujii H,Campana D,Kono K.Therapeutic potential of highly cytotoxic natural killer cells for gastric cancer.Int J Cancer 2014;135:1390-1398[PMID:24615495DOI:10.1002/ijc.28780]
    71 Wakatsuki K,Sho M,Yamato I,Takayama T,Matsumoto S,Tanaka T,Migita K,Ito M,Hotta K,Nakajima Y.Clinical impact of tumorinfiltrating CD45RO+memory T cells on human gastric cancer.Oncol Rep 2013;29:1756-1762[PMID:23440298 DOI:10.3892/or.2013.2302]
    72 Chen LJ,Zheng X,Shen YP,Zhu YB,Li Q,Chen J,Xia R,Zhou SM,Wu CP,Zhang XG,Lu BF,Jiang JT.Higher numbers of T-bet(+)intratumoral lymphoid cells correlate with better survival in gastric cancer.Cancer Immunol Immunother 2013;62:553-561[PMID:23090288 DOI:10.1007/s00262-012-1358-6]
    73 Hennequin A,Derangère V,Boidot R,Apetoh L,Vincent J,Orry D,Fraisse J,Causeret S,Martin F,Arnould L,Beltjens F,Ghiringhelli F,Ladoire S.Tumor infiltration by Tbet+effector T cells and CD20+B cells is associated with survival in gastric cancer patients.Oncoimmunology 2015;5:e1054598[PMID:27057426 DOI:10.1080/2162402X.2015.1054598]
    74 Arigami T,Uenosono Y,Ishigami S,Matsushita D,Hirahara T,Yanagita S,Okumura H,Uchikado Y,Nakajo A,Kijima Y,Natsugoe S.Decreased density of CD3+tumor-infiltrating lymphocytes during gastric cancer progression.J Gastroenterol Hepatol 2014;29:1435-1441[PMID:25587614 DOI:10.1111/jgh.12551]
    75 Michie CA,Mc Lean A,Alcock C,Beverley PC.Lifespan of human lymphocyte subsets defined by CD45 isoforms.Nature 1992;360:264-265[PMID:1436108 DOI:10.1038/360264a0]
    76 Fossiez F,Djossou O,Chomarat P,Flores-Romo L,Ait-Yahia S,Maat C,Pin JJ,Garrone P,Garcia E,Saeland S,Blanchard D,Gaillard C,Das Mahapatra B,Rouvier E,Golstein P,Banchereau J,Lebecque S.T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines.J Exp Med 1996;183:2593-2603[PMID:8676080 DOI:10.1084/jem.183.6.2593]
    77 Benchetrit F,Ciree A,Vives V,Warnier G,Gey A,Sautès-Fridman C,Fossiez F,Haicheur N,Fridman WH,Tartour E.Interleukin-17inhibits tumor cell growth by means of a T-cell-dependent mechanism.Blood 2002;99:2114-2121[PMID:11877287 DOI:10.1182/blood.V99.6.2114]
    78 Antonysamy MA,Fanslow WC,Fu F,Li W,Qian S,Troutt AB,Thomson AW.Evidence for a role of IL-17 in organ allograft rejection:IL-17 promotes the functional differentiation of dendritic cell progenitors.J Immunol 1999;162:577-584[PMID:9886435]
    79 Yuan L,Xu B,Yuan P,Zhou J,Qin P,Han L,Chen G,Wang Z,Run Z,Zhao P,Gao Q.Tumor-infiltrating CD4+T cells in patients with gastric cancer.Cancer Cell Int 2017;17:114[PMID:29213216DOI:10.1186/s12935-017-0489-4]
    80 Choi HS,Ha SY,Kim HM,Ahn SM,Kang MS,Kim KM,Choi MG,Lee JH,Sohn TS,Bae JM,Kim S,Kang ES.The prognostic effects of tumor infiltrating regulatory T cells and myeloid derived suppressor cells assessed by multicolor flow cytometry in gastric cancer patients.Oncotarget 2016;7:7940-7951[PMID:26799288DOI:10.18632/oncotarget.6958]
    81 Raziorrouh B,Ulsenheimer A,Schraut W,Heeg M,Kurktschiev P,Zachoval R,Jung MC,Thimme R,Neumann-Haefelin C,Horster S,W?chtler M,Spannagl M,Haas J,Diepolder HM,Grüner NH.Inhibitory molecules that regulate expansion and restoration of HCV-specific CD4+T cells in patients with chronic infection.Gastroenterology 2011;141:1422-1431,1431.e1-1431.e6[PMID:21763239 DOI:10.1053/j.gastro.2011.07.004]
    82 Xu B,Yuan L,Gao Q,Yuan P,Zhao P,Yuan H,Fan H,Li T,Qin P,Han L,Fang W,Suo Z.Circulating and tumor-infiltrating Tim-3 in patients with colorectal cancer.Oncotarget 2015;6:20592-20603[PMID:26008981 DOI:10.18632/oncotarget.4112]
    83 Figdor CG,de Vries IJ,Lesterhuis WJ,Melief CJ.Dendritic cell immunotherapy:mapping the way.Nat Med 2004;10:475-480[PMID:15122249 DOI:10.1038/nm1039]
    84 Tsujitani S,Kakeji Y,Orita H,Watanabe A,Kohnoe S,Baba H,Anai H,Maehara Y,Sugimachi K.Postoperative adjuvant immunochemotherapy and infiltration of dendritic cells for patients with advanced gastric cancer.Anticancer Res 1992;12:645-648[PMID:1622120]
    85 Teng MW,Ngiow SF,Ribas A,Smyth MJ.Classifying Cancers Based on T-cell Infiltration and PD-L1.Cancer Res 2015;75:2139-2145[PMID:25977340 DOI:10.1158/0008-5472.CAN-15-0255]
    86 Tumeh PC,Harview CL,Yearley JH,Shintaku IP,Taylor EJ,Robert L,Chmielowski B,Spasic M,Henry G,Ciobanu V,West AN,Carmona M,Kivork C,Seja E,Cherry G,Gutierrez AJ,Grogan TR,Mateus C,Tomasic G,Glaspy JA,Emerson RO,Robins H,Pierce RH,Elashoff DA,Robert C,Ribas A.PD-1 blockade induces responses by inhibiting adaptive immune resistance.Nature 2014;515:568-571[PMID:25428505 DOI:10.1038/nature13954]
    87 Ma J,Li J,Hao Y,Nie Y,Li Z,Qian M,Liang Q,Yu J,Zeng M,Wu K.Differentiated tumor immune microenvironment of EpsteinBarr virus-associated and negative gastric cancer:implication in prognosis and immunotherapy.Oncotarget 2017;8:67094-67103[PMID:28978018 DOI:10.18632/oncotarget.17945]
    88 Grogg KL,Lohse CM,Pankratz VS,Halling KC,Smyrk TC.Lymphocyte-rich gastric cancer:associations with Epstein-Barr virus,microsatellite instability,histology,and survival.Mod Pathol 2003;16:641-651[PMID:12861059 DOI:10.1097/01.MP.0000076980.73826.C0]
    89 Ghiringhelli F,Ménard C,Terme M,Flament C,Taieb J,Chaput N,Puig PE,Novault S,Escudier B,Vivier E,Lecesne A,Robert C,Blay JY,Bernard J,Caillat-Zucman S,Freitas A,Tursz T,WagnerBallon O,Capron C,Vainchencker W,Martin F,Zitvogel L.CD4+CD25+regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner.J Exp Med 2005;202:1075-1085[PMID:16230475 DOI:10.1084/jem.20051511]
    90 Wang L,Chang EW,Wong SC,Ong SM,Chong DQ,Ling KL.Increased myeloid-derived suppressor cells in gastric cancer correlate with cancer stage and plasma S100A8/A9 proinflammatory proteins.J Immunol 2013;190:794-804[PMID:23248262 DOI:10.4049/jimmunol.1202088]
    91 Almand B,Clark JI,Nikitina E,van Beynen J,English NR,Knight SC,Carbone DP,Gabrilovich DI.Increased production of immature myeloid cells in cancer patients:a mechanism of immunosuppression in cancer.J Immunol 2001;166:678-689[PMID:11123353 DOI:10.4049/jimmunol.166.1.678]
    92 Shoji H,Tada K,Kitano S,Nishimura T,Shimada Y,Nagashima K,Aoki K,Hiraoka N,Honma Y,Iwasa S,Takashima A,Kato K,Boku N,Honda K,Yamada T,Heike Y,Hamaguchi T.The peripheral immune status of granulocytic myeloid-derived suppressor cells correlates the survival in advanced gastric cancer patients receiving cisplatin-based chemotherapy.Oncotarget 2017;8:95083-95094[PMID:29221113 DOI:10.18632/oncotarget.18297]
    93 Asfaha S,Dubeykovskiy AN,Tomita H,Yang X,Stokes S,Shibata W,Friedman RA,Ariyama H,Dubeykovskaya ZA,Muthupalani S,Ericksen R,Frucht H,Fox JG,Wang TC.Mice that express human interleukin-8 have increased mobilization of immature myeloid cells,which exacerbates inflammation and accelerates colon carcinogenesis.Gastroenterology 2013;144:155-166[PMID:23041326 DOI:10.1053/j.gastro.2012.09.057]
    94 Chi N,Tan Z,Ma K,Bao L,Yun Z.Increased circulating myeloidderived suppressor cells correlate with cancer stages,interleukin-8and-6 in prostate cancer.Int J Clin Exp Med 2014;7:3181-3192[PMID:25419348]
    95 Coussens LM,Werb Z.Inflammation and cancer.Nature 2002;420:860-867[PMID:12490959 DOI:10.1038/nature01322]
    96 Grivennikov SI,Greten FR,Karin M.Immunity,inflammation,and cancer.Cell 2010;140:883-899[PMID:20303878 DOI:10.1016/j.cell.2010.01.025]
    97 Mc Millan DC.Systemic inflammation,nutritional status and survival in patients with cancer.Curr Opin Clin Nutr Metab Care 2009;12:223-226[PMID:19318937 DOI:10.1097/MCO.0b013e32832a7902]
    98 Zahorec R.Ratio of neutrophil to lymphocyte counts--rapid and simple parameter of systemic inflammation and stress in critically ill.Bratisl Lek Listy 2001;102:5-14[PMID:11723675]
    99 Shibata M,Nezu T,Kanou H,Abe H,Takekawa M,Fukuzawa M.Decreased production of interleukin-12 and type 2 immune responses are marked in cachectic patients with colorectal and gastric cancer.J Clin Gastroenterol 2002;34:416-420[PMID:11907352DOI:10.1097/00004836-200204000-00006]
    100 Ohki S,Shibata M,Gonda K,Machida T,Shimura T,Nakamura I,Ohtake T,Koyama Y,Suzuki S,Ohto H,Takenoshita S.Circulating myeloid-derived suppressor cells are increased and correlate to immune suppression,inflammation and hypoproteinemia in patients with cancer.Oncol Rep 2012;28:453-458[PMID:22614133 DOI:10.3892/or.2012.1812]
    101 Gonda K,Shibata M,Sato Y,Washio M,Takeshita H,Shigeta H,Ogura M,Oka S,Sakuramoto S.Elevated neutrophil-to-lymphocyte ratio is associated with nutritional impairment,immune suppression,resistance to S-1 plus cisplatin,and poor prognosis in patients with stageⅣgastric cancer.Mol Clin Oncol 2017;7:1073-1078[PMID:29285377 DOI:10.3892/mco.2017.1438]
    102 Mc Carthy EF.The toxins of William B.Coley and the treatment of bone and soft-tissue sarcomas.Iowa Orthop J 2006;26:154-158[PMID:16789469]
    103 Niccolai E,Taddei A,Prisco D,Amedei A.Gastric cancer and the epoch of immunotherapy approaches.World J Gastroenterol 2015;21:5778-5793[PMID:26019442 DOI:10.3748/wjg.v21.i19.5778]
    104 Bonotto M,Garattini SK,Basile D,Ongaro E,Fanotto V,Cattaneo M,Cortiula F,Iacono D,Cardellino GG,Pella N,Fasola G,Antonuzzo L,Silvestris N,Aprile G.Immunotherapy for gastric cancers:emerging role and future perspectives.Expert Rev Clin Pharmacol 2017;10:609-619[PMID:28349740 DOI:10.1080/17512433.2017.1313113]
    105 Chen L,Flies DB.Molecular mechanisms of T cell co-stimulation and co-inhibition.Nat Rev Immunol 2013;13:227-242[PMID:23470321 DOI:10.1038/nri3405]
    106 Hanna MG Jr,Hoover HC Jr,Vermorken JB,Harris JE,Pinedo HM.Adjuvant active specific immunotherapy of stageⅡand stageⅢcolon cancer with an autologous tumor cell vaccine:first randomized phaseⅢtrials show promise.Vaccine 2001;19:2576-2582[PMID:11257395 DOI:10.1016/S0264-410X(00)00485-0]
    107 Derouazi M,Di Berardino-Besson W,Belnoue E,Hoepner S,Walther R,Benkhoucha M,Teta P,Dufour Y,Yacoub Maroun C,Salazar AM,Martinvalet D,Dietrich PY,Walker PR.Novel CellPenetrating Peptide-Based Vaccine Induces Robust CD4+and CD8+T Cell-Mediated Antitumor Immunity.Cancer Res 2015;75:3020-3031[PMID:26116496 DOI:10.1158/0008-5472.CAN-14-3017]
    108 Rosenberg SA,Yang JC,Sherry RM,Kammula US,Hughes MS,Phan GQ,Citrin DE,Restifo NP,Robbins PF,Wunderlich JR,Morton KE,Laurencot CM,Steinberg SM,White DE,Dudley ME.Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy.Clin Cancer Res 2011;17:4550-4557[PMID:21498393 DOI:10.1158/1078-0432.CCR-11-0116]
    109 Nie Y,Wu K,Yang J,Tian F,Li L,Chen B,Fan D.Induction of Tlymphocytes specific to human gastric cancer using HLA-A matched allogeneic gastric tumor cells.J Immunother 2003;26:403-411[PMID:12973029]
    110 Kawamoto M,Tanaka F,Mimori K,Inoue H,Kamohara Y,Mori M.Identification of HLA-A*0201/-A*2402-restricted CTL epitopepeptides derived from a novel cancer/testis antigen,MCAK,and induction of a specific antitumor immune response.Oncol Rep 2011;25:469-476[PMID:21165574 DOI:10.3892/or.2010.1101]
    111 Kono K,Ichihara F,Iizuka H,Sekikawa T,Matsumoto Y.Differences in the recognition of tumor-specific CD8+T cells derived from solid tumor,metastatic lymph nodes and ascites in patients with gastric cancer.Int J Cancer 1997;71:978-981[PMID:9185700]
    112 Fujie T,Tanaka F,Tahara K,Li J,Tanaka S,Mori M,Ueo H,Takesako K,Akiyoshi T.Generation of specific antitumor reactivity by the stimulation of spleen cells from gastric cancer patients with MAGE-3 synthetic peptide.Cancer Immunol Immunother 1999;48:189-194[PMID:10431688]
    113 Sun S,Li XM,Li XD,Yang WS.Studies on inducing apoptosis effects and mechanism of CIK cells for MGC-803 gastric cancer cell lines.Cancer Biother Radiopharm 2005;20:173-180[PMID:15869451 DOI:10.1089/cbr.2005.20.173]
    114 Kim YJ,Lim J,Kang JS,Kim HM,Lee HK,Ryu HS,Kim JY,Hong JT,Kim Y,Han SB.Adoptive immunotherapy of human gastric cancer with ex vivo expanded T cells.Arch Pharm Res 2010;33:1789-1795[PMID:21116782 DOI:10.1007/s12272-010-1111-7]
    115 Bourquin C,von der Borch P,Zoglmeier C,Anz D,Sandholzer N,Suhartha N,Wurzenberger C,Denzel A,Kammerer R,Zimmermann W,Endres S.Efficient eradication of subcutaneous but not of autochthonous gastric tumors by adoptive T cell transfer in an SV40T antigen mouse model.J Immunol 2010;185:2580-2588[PMID:20644173 DOI:10.4049/jimmunol.0903231]
    116 Gebremeskel S,Johnston B.Concepts and mechanisms underlying chemotherapy induced immunogenic cell death:impact on clinical studies and considerations for combined therapies.Oncotarget 2015;6:41600-41619[PMID:26486085 DOI:10.18632/oncotarget.6113]
    117 Zhao Q,Zhang H,Li Y,Liu J,Hu X,Fan L.Anti-tumor effects of CIK combined with oxaliplatin in human oxaliplatin-resistant gastric cancer cells in vivo and in vitro.J Exp Clin Cancer Res 2010;29:118[PMID:20799994 DOI:10.1186/1756-9966-29-118]
    118 Dudley ME,Wunderlich JR,Robbins PF,Yang JC,Hwu P,Schwartzentruber DJ,Topalian SL,Sherry R,Restifo NP,Hubicki AM,Robinson MR,Raffeld M,Duray P,Seipp CA,Rogers-Freezer L,Morton KE,Mavroukakis SA,White DE,Rosenberg SA.Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes.Science 2002;298:850-854[PMID:12242449 DOI:10.1126/science.1076514]
    119 Kobold S,Steffen J,Chaloupka M,Grassmann S,Henkel J,Castoldi R,Zeng Y,Chmielewski M,Schmollinger JC,Schnurr M,Rothenfu?er S,Schendel DJ,Abken H,Sustmann C,Niederfellner G,Klein C,Bourquin C,Endres S.Selective bispecific T cell recruiting antibody and antitumor activity of adoptive T cell transfer.J Natl Cancer Inst 2014;107:364[PMID:25424197 DOI:10.1093/jnci/dju364]
    120 Du X,Jin R,Ning N,Li L,Wang Q,Liang W,Liu J,Xu Y.In vivo distribution and antitumor effect of infused immune cells in a gastric cancer model.Oncol Rep 2012;28:1743-1749[PMID:22948809DOI:10.3892/or.2012.2013]
    121 Kevin T,Mark H,Craig L,inventors;Alan J,assignee;Cytotoxic T Lymphocyte-stimulation peptides for prevention,treatment,and diagnosis of melanoma.International patent WO2001032193.2001May 10
    122 Bhatia S,Tykodi SS,Thompson JA.Treatment of metastatic melanoma:an overview.Oncology(Williston Park)2009;23:488-496[PMID:19544689]
    123 Yee C,Thompson JA,Byrd D,Riddell SR,Roche P,Celis E,Greenberg PD.Adoptive T cell therapy using antigen-specific CD8+T cell clones for the treatment of patients with metastatic melanoma:in vivo persistence,migration,and antitumor effect of transferred T cells.Proc Natl Acad Sci U S A 2002;99:16168-16173[PMID:12427970 DOI:10.1073/pnas.242600099]
    124 Rosenberg SA,Lotze MT,Muul LM,Chang AE,Avis FP,Leitman S,Linehan WM,Robertson CN,Lee RE,Rubin JT.A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone.N Engl J Med 1987;316:889-897[PMID:3493432]
    125 Zhang GQ,Zhao H,Wu JY,Li JY,Yan X,Wang G,Wu LL,Zhang XG,Shao Y,Wang Y,Jiao SC.Prolonged overall survival in gastric cancer patients after adoptive immunotherapy.World J Gastroenterol2015;21:2777-2785[PMID:25759549 DOI:10.3748/wjg.v21.i9.2777]
    126 Zhao H,Fan Y,Li H,Yu J,Liu L,Cao S,Ren B,Yan F,Ren X.Immunotherapy with cytokine-induced killer cells as an adjuvant treatment for advanced gastric carcinoma:a retrospective study of165 patients.Cancer Biother Radiopharm 2013;28:303-309[PMID:23506427 DOI:10.1089/cbr.2012.1306]
    127 Chen Y,Guo ZQ,Shi CM,Zhou ZF,Ye YB,Chen Q.Efficacy of adjuvant chemotherapy combined with immunotherapy with cytokine-induced killer cells for gastric cancer after d2 gastrectomy.Int J Clin Exp Med 2015;8:7728-7736[PMID:26221323]
    128 Shi L,Zhou Q,Wu J,Ji M,Li G,Jiang J,Wu C.Efficacy of adjuvant immunotherapy with cytokine-induced killer cells in patients with locally advanced gastric cancer.Cancer Immunol Immunother 2012;61:2251-2259[PMID:22674056 DOI:10.1007/s00262-012-1289-2]
    129 Jiang J,Xu N,Wu C,Deng H,Lu M,Li M,Xu B,Wu J,Wang R,Xu J,Nilsson-Ehle P.Treatment of advanced gastric cancer by chemotherapy combined with autologous cytokine-induced killer cells.Anticancer Res 2006;26:2237-2242[PMID:16821594]
    130 Jiang JT,Shen YP,Wu CP,Zhu YB,Wei WX,Chen LJ,Zheng X,Sun J,Lu BF,Zhang XG.Increasing the frequency of CIK cells adoptive immunotherapy may decrease risk of death in gastric cancer patients.World J Gastroenterol 2010;16:6155-6162[PMID:21182234 DOI:10.3748/wjg.v16.i48.6155]
    131 J?kel CE,Vogt A,Gonzalez-Carmona MA,Schmidt-Wolf IG.Clinical studies applying cytokine-induced killer cells for the treatment of gastrointestinal tumors.J Immunol Res 2014;2014:897214[PMID:24741629 DOI:10.1155/2014/897214]
    132 Wada I,Matsushita H,Noji S,Mori K,Yamashita H,Nomura S,Shimizu N,Seto Y,Kakimi K.Intraperitoneal injection of in vitro expanded Vγ9Vδ2 T cells together with zoledronate for the treatment of malignant ascites due to gastric cancer.Cancer Med 2014;3:362-375[PMID:24515916 DOI:10.1002/cam4.196]
    133 Cellular Biomedicine Group Ltd.The Study of Surgery,Chemotherapy and Autologous T Cells-Based Immunotherapy for Advanced Gastric Cancer.[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:http://clinicaltrials.gov/show/NCT02704299Clinical Trials.gov Identifier:NCT02704299
    134 Shenzhen Hornetcorn Bio-technology Company,LTD.“Study of Autologous Tumor Lysate-pulsed D-CIK Combined With Chemotherapy for Gastric Cancer”.[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:http://clinicaltrials.gov/show/NCT02215837 Clinical Trials.gov Identifier:NCT02215837
    135 First Affiliated Hospital of Chengdu Medical College.AClinical Research of CAR T Cells Targeting Ep CAMPositive Cancer(CARTEPC).[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:http://clinicaltrials.gov/show/NCT03013712Clinical Trials.gov Identifier:NCT03013712
    136 Person Gen Bio Therapeutics(Suzhou)Co.,Ltd.CAR-T Cell Immunotherapy in MUC1 Positive Solid Tumor.[accessed 2018 May4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:http://clinicaltrials.gov/show/NCT02617134 Clinical Trials.gov Identifier:NCT02617134
    137 Roger Williams Medical Center.CAR-T Hepatic Artery Infusions for CEA-Expressing Liver Metastases(HITM-SURE).[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:http://clinicaltrials.gov/show/NCT02850536 Clinical Trials.gov Identifier:NCT02850536
    138 University SMM,Immunotherapy Using Pluripotent Killer-Human Epidermal Growth Factor Receptor-2(PIK-HER2)Cells for the Treatment of Advanced Gastric Cancer With Liver Metastasis.[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:http://clinicaltrials.gov/show/NCT02632201 Clinical Trials.gov Identifier:NCT02632201
    139 Miao Y.T Cell Mediated Adaptive therapy for Her2-positive Neoplasms of Digestive System,in Clinical Trials.gov[Internet],Bethesda(MD):National Library of Medicine(US),2000 Available from:URL:http://clinicaltrials.gov/show/NCT02662348
    140 Capital Medical University.Study of S-1 Plus DC-CIK for Patients With Advanced Gastric Cancer.[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:http://clinicaltrials.gov/show/NCT01783951 Clinical Trials.gov Identifier:NCT01783951
    141 Dudley ME,Wunderlich JR,Shelton TE,Even J,Rosenberg SA.Generation of tumor-infiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients.J Immunother2003;26:332-342[PMID:12843795 DOI:10.1097/00002371-200307000-00005]
    142 Alexander RB,Rosenberg SA.Long-term survival of adoptively transferred tumor-infiltrating lymphocytes in mice.J Immunol 1990;145:1615-1620[PMID:1974569]
    143 Kono K,Takahashi A,Ichihara F,Amemiya H,Iizuka H,Fujii H,Sekikawa T,Matsumoto Y.Prognostic significance of adoptive immunotherapy with tumor-associated lymphocytes in patients with advanced gastric cancer:a randomized trial.Clin Cancer Res 2002;8:1767-1771[PMID:12060615]
    144 Rosenberg SA,Yannelli JR,Yang JC,Topalian SL,Schwartzentruber DJ,Weber JS,Parkinson DR,Seipp CA,Einhorn JH,White DE.Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2.J Natl Cancer Inst1994;86:1159-1166[PMID:8028037 DOI:10.1093/jnci/86.15.1159]
    145 Amedei A,Munari F,Bella CD,Niccolai E,Benagiano M,Bencini L,Cianchi F,Farsi M,Emmi G,Zanotti G,de Bernard M,Kundu M,D’Elios MM.Helicobacter pylori secreted peptidyl prolyl cis,transisomerase drives Th17 inflammation in gastric adenocarcinoma.Intern Emerg Med 2014;9:303-309[PMID:23054412 DOI:10.1007/s11739-012-0867-9]
    146 Yamaue H,Tanimura H,Tsunoda T,Iwahashi M,Tani M,Inoue M,Tamai M.[Clinical application of adoptive immunotherapy by cytotoxic T lymphocytes induced from tumor-infiltrating lymphocytes].Nihon Gan Chiryo Gakkai Shi 1990;25:978-989[PMID:2391445]
    147 Voskens CJ,Watanabe R,Rollins S,Campana D,Hasumi K,Mann DL.Ex-vivo expanded human NK cells express activating receptors that mediate cytotoxicity of allogeneic and autologous cancer cell lines by direct recognition and antibody directed cellular cytotoxicity.J Exp Clin Cancer Res 2010;29:134[PMID:20937115 DOI:10.1186/1756-9966-29-134]
    148 Langers I,Renoux VM,Thiry M,Delvenne P,Jacobs N.Natural killer cells:role in local tumor growth and metastasis.Biologics2012;6:73-82[PMID:22532775 DOI:10.2147/BTT.S23976]
    149 Kim S,Iizuka K,Aguila HL,Weissman IL,Yokoyama WM.In vivo natural killer cell activities revealed by natural killer celldeficient mice.Proc Natl Acad Sci USA 2000;97:2731-2736[PMID:10694580 DOI:10.1073/pnas.050588297]
    150 Coca S,Perez-Piqueras J,Martinez D,Colmenarejo A,Saez MA,Vallejo C,Martos JA,Moreno M.The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma.Cancer 1997;79:2320-2328[PMID:9191519 DOI:10.1002/(SICI)1097-0142(19970615)79:12<2320::AID-CNCR5>3.0.CO;2-P]
    151 Rosso D,Rigueiro MP,Kassab P,Ilias EJ,Castro OA,Novo NF,Louren?o LG.[Correlation of natural killer cells with the prognosis of gastric adenocarcinoma].Arq Bras Cir Dig 2012;25:114-117[PMID:23381755 DOI:10.1590/S0102-67202012000200011]
    152 Saito H,Takaya S,Osaki T,Ikeguchi M.Increased apoptosis and elevated Fas expression in circulating natural killer cells in gastric cancer patients.Gastric Cancer 2013;16:473-479[PMID:23179366 DOI:10.1007/s10120-012-0210-1]
    153 Cui J,Li L,Wang C,Jin H,Yao C,Wang Y,Li D,Tian H,Niu C,Wang G,Han W,Xu J,Chen J,Li W.Combined cellular immunotherapy and chemotherapy improves clinical outcome in patients with gastric carcinoma.Cytotherapy 2015;17:979-988[PMID:25890480 DOI:10.1016/j.jcyt.2015.03.605]
    154 National University Hospital,Singapore.NK cell infusions with trastuzumab for patients with HER2+breast and gastric cancer”.[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:http://clinicaltrials.gov/show/NCT02030561 Clinical Trials.gov Identifier:NCT02030561
    155 Wu XT,Liu JQ,Lu XT,Chen FX,Zhou ZH,Wang T,Zhu SP,Fei SJ.The enhanced effect of lupeol on the destruction of gastric cancer cells by NK cells.Int Immunopharmacol 2013;16:332-340[PMID:23639256 DOI:10.1016/j.intimp.2013.04.017]
    156 Kono K,Rongcun Y,Charo J,Ichihara F,Celis E,Sette A,Appella E,Sekikawa T,Matsumoto Y,Kiessling R.Identification of HER2/neu-derived peptide epitopes recognized by gastric cancer-specific cytotoxic T lymphocytes.Int J Cancer 1998;78:202-208[PMID:9754653 DOI:10.1002/(SICI)1097-0215(19981005)78:2<202::AID-IJC14>3.0.CO;2-C]
    157 Tanaka F,Fujie T,Tahara K,Mori M,Takesako K,Sette A,Celis E,Akiyoshi T.Induction of antitumor cytotoxic T lymphocytes with a MAGE-3-encoded synthetic peptide presented by human leukocytes antigen-A24.Cancer Res 1997;57:4465-4468[PMID:9377553]
    158 Higashihara Y,Kato J,Nagahara A,Izumi K,Konishi M,Kodani T,Serizawa N,Osada T,Watanabe S.Phase I clinical trial of peptide vaccination with URLC10 and VEGFR1 epitope peptides in patients with advanced gastric cancer.Int J Oncol 2014;44:662-668[PMID:24398900 DOI:10.3892/ijo.2013.2242]
    159 Gang Y,Zhang X,He Y,Zheng J,Wu K,Ding J,Fan D.Efficient induction of specific cytotoxic T lymphocytes against gastric adenocarcinoma by a survivin peptide.Biochem Cell Biol 2012;90:701-708[PMID:22992138 DOI:10.1139/o2012-028]
    160 Zhang K,Peng Z,Huang X,Qiao Z,Wang X,Wang N,Xi H,Cui J,Gao Y,Huang X,Gao H,Wei B,Chen L.Phase II Trial of Adjuvant Immunotherapy with Autologous Tumor-derived Gp96 Vaccination in Patients with Gastric Cancer.J Cancer 2017;8:1826-1832[PMID:28819380 DOI:10.7150/jca.18946]
    161 Celluzzi CM,Mayordomo JI,Storkus WJ,Lotze MT,Falo LD Jr.Peptide-pulsed dendritic cells induce antigen-specific CTL-mediated protective tumor immunity.J Exp Med 1996;183:283-287[PMID:8551233 DOI:10.1084/jem.183.1.283]
    162 Gilboa E.DC-based cancer vaccines.J Clin Invest 2007;117:1195-1203[PMID:17476349 DOI:10.1172/JCI31205]
    163 Yang J,Li ZH,Zhou JJ,Chen RF,Cheng LZ,Zhou QB,Yang LQ.Preparation and antitumor effects of nanovaccines with MAGE-3peptides in transplanted gastric cancer in mice.Chin J Cancer 2010;29:359-364[PMID:20346208 DOI:10.5732/cjc.009.10541]
    164 Galetto A,Contarini M,Sapino A,Cassoni P,Consalvo E,Forno S,Pezzi C,Barnaba V,Mussa A,Matera L.Ex vivo host response to gastrointestinal cancer cells presented by autologous dendritic cells.J Surg Res 2001;100:32-38[PMID:11516202 DOI:10.1006/jsre.2001.6158]
    165 Kreiter S,Selmi A,Diken M,Koslowski M,Britten CM,Huber C,Türeci O,Sahin U.Intranodal vaccination with naked antigenencoding RNA elicits potent prophylactic and therapeutic antitumoral immunity.Cancer Res 2010;70:9031-9040[PMID:21045153 DOI:10.1158/0008-5472.CAN-10-0699]
    166 Fotin-Mleczek M,Duchardt KM,Lorenz C,Pfeiffer R,Ojki?-Zrna S,Probst J,Kallen KJ.Messenger RNA-based vaccines with dual activity induce balanced TLR-7 dependent adaptive immune responses and provide antitumor activity.J Immunother 2011;34:1-15[PMID:21150709 DOI:10.1097/CJI.0b013e3181f7dbe8]
    167 Weide B,Carralot JP,Reese A,Scheel B,Eigentler TK,Hoerr I,Rammensee HG,Garbe C,Pascolo S.Results of the first phase I/II clinical vaccination trial with direct injection of m RNA.JImmunother 2008;31:180-188[PMID:18481387 DOI:10.1097/CJI.0b013e31815ce501]
    168 Weide B,Pascolo S,Scheel B,Derhovanessian E,Pflugfelder A,Eigentler TK,Pawelec G,Hoerr I,Rammensee HG,Garbe C.Direct injection of protamine-protected m RNA:results of a phase 1/2 vaccination trial in metastatic melanoma patients.JImmunother 2009;32:498-507[PMID:19609242 DOI:10.1097/CJI.0b013e3181a00068]
    169 Kim TW,Hung CF,Ling M,Juang J,He L,Hardwick JM,Kumar S,Wu TC.Enhancing DNA vaccine potency by coadministration of DNA encoding antiapoptotic proteins.J Clin Invest 2003;112:109-117[PMID:12840065 DOI:10.1172/JCI17293]
    170 Leslie NR,Batty IH,Maccario H,Davidson L,Downes CP.Understanding PTEN regulation:PIP2,polarity and protein stability.Oncogene 2008;27:5464-5476[PMID:18794881 DOI:10.1038/onc.2008.243]
    171 Kim JH,Kang TH,Noh KH,Kim SH,Lee YH,Kim KW,Bae HC,Ahn YH,Choi EY,Kim JS,Lee KM,Kim TW.Enhancement of DCvaccine potency by activating the PI3K/AKT pathway with a small interfering RNA targeting PTEN.Immunol Lett 2010;134:47-54[PMID:20727912 DOI:10.1016/j.imlet.2010.08.008]
    172 Kim JH,Kang TH,Noh KH,Bae HC,Ahn YH,Lee YH,Choi EY,Chun KH,Lee SJ,Kim TW.Blocking the immunosuppressive axis with small interfering RNA targeting interleukin(IL)-10receptor enhances dendritic cell-based vaccine potency.Clin Exp Immunol 2011;165:180-189[PMID:21592111 DOI:10.1111/j.1365-2249.2011.04410.x]
    173 He SB,Sun K,Wang L,Li DC,Zhang YY.[GM-CSF gene-modified dendritic cell vaccine enhances antitumor immunity in vitro].Zhonghua Zhong Liu Za Zhi 2010;32:410-414[PMID:20819479]
    174 Dannull J,Su Z,Rizzieri D,Yang BK,Coleman D,Yancey D,Zhang A,Dahm P,Chao N,Gilboa E,Vieweg J.Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells.J Clin Invest 2005;115:3623-3633[PMID:16308572 DOI:10.1172/JCI25947]
    175 Popiela T,Kulig J,Czupryna A,Szczepanik AM,Zembala M.Efficiency of adjuvant immunochemotherapy following curative resection in patients with locally advanced gastric cancer.Gastric Cancer 2004;7:240-245[PMID:15616772 DOI:10.1007/s10120-004-0299-y]
    176 Ajani JA,Hecht JR,Ho L,Baker J,Oortgiesen M,Eduljee A,Michaeli D.An open-label,multinational,multicenter study of G17DT vaccination combined with cisplatin and 5-fluorouracil in patients with untreated,advanced gastric or gastroesophageal cancer:the GC4 study.Cancer 2006;106:1908-1916[PMID:16568451DOI:10.1002/cncr.21814]
    177 Masuzawa T,Fujiwara Y,Okada K,Nakamura A,Takiguchi S,Nakajima K,Miyata H,Yamasaki M,Kurokawa Y,Osawa R,Takeda K,Yoshida K,Tsunoda T,Nakamura Y,Mori M,Doki Y.Phase I/II study of S-1 plus cisplatin combined with peptide vaccines for human vascular endothelial growth factor receptor 1 and 2 in patients with advanced gastric cancer.Int J Oncol 2012;41:1297-1304[PMID:22842485 DOI:10.3892/ijo.2012.1573]
    178 Finn OJ.Cancer immunology.N Engl J Med 2008;358:2704-2715[PMID:18565863 DOI:10.1056/NEJMra072739]
    179 Simpson TR,Li F,Montalvo-Ortiz W,Sepulveda MA,Bergerhoff K,Arce F,Roddie C,Henry JY,Yagita H,Wolchok JD,Peggs KS,Ravetch JV,Allison JP,Quezada SA.Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.J Exp Med 2013;210:1695-1710[PMID:23897981 DOI:10.1084/jem.20130579]
    180 Freeman GJ,Long AJ,Iwai Y,Bourque K,Chernova T,Nishimura H,Fitz LJ,Malenkovich N,Okazaki T,Byrne MC,Horton HF,Fouser L,Carter L,Ling V,Bowman MR,Carreno BM,Collins M,Wood CR,Honjo T.Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation.J Exp Med 2000;192:1027-1034[PMID:11015443 DOI:10.1084/jem.192.7.1027]
    181 Wang J,Yuan R,Song W,Sun J,Liu D,Li Z.PD-1,PD-L1(B7-H1)and Tumor-Site Immune Modulation Therapy:The Historical Perspective.J Hematol Oncol 2017;10:34[PMID:28122590 DOI:10.1186/s13045-017-0403-5]
    182 Brahmer JR,Tykodi SS,Chow LQ,Hwu WJ,Topalian SL,Hwu P,Drake CG,Camacho LH,Kauh J,Odunsi K,Pitot HC,Hamid O,Bhatia S,Martins R,Eaton K,Chen S,Salay TM,Alaparthy S,Grosso JF,Korman AJ,Parker SM,Agrawal S,Goldberg SM,Pardoll DM,Gupta A,Wigginton JM.Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.N Engl J Med 2012;366:2455-2465[PMID:22658128 DOI:10.1056/NEJMoa1200694]
    183 Savabkar S,Azimzadeh P,Chaleshi V,Nazemalhosseini Mojarad E,Aghdaei HA.Programmed death-1 gene polymorphism(PD-1.5 C/T)is associated with gastric cancer.Gastroenterol Hepatol Bed Bench2013;6:178-182[PMID:24834269]
    184 Tang W,Chen Y,Chen S,Sun B,Gu H,Kang M.Programmed death-1(PD-1)polymorphism is associated with gastric cardia adenocarcinoma.Int J Clin Exp Med 2015;8:8086-8093[PMID:26221374]
    185 Yan Q,Chen P,Lu A,Zhao P,Gu A.Association between CTLA-460G/A and-1661A/G polymorphisms and the risk of cancers:a meta-analysis.PLo S One 2013;8:e83710[PMID:24376736 DOI:10.1371/journal.pone.0083710]
    186 Kordi-Tamandani DM,Davani SK,Baranzehi T,Hemati S.Analysis of promoter methylation,polymorphism and expression profile of cytotoxic T-lymphocyte-associated antigen-4 in patients with gastric cancer.J Gastrointestin Liver Dis 2014;23:249-253[PMID:25267951 DOI:10.15403/jgld.2014.1121.233.dmkt]
    187 Saito H,Kuroda H,Matsunaga T,Osaki T,Ikeguchi M.Increased PD-1 expression on CD4+and CD8+T cells is involved in immune evasion in gastric cancer.J Surg Oncol 2013;107:517-522[PMID:23129549 DOI:10.1002/jso.23281]
    188 Wu C,Zhu Y,Jiang J,Zhao J,Zhang XG,Xu N.Immunohistochemical localization of programmed death-1 ligand-1(PD-L1)in gastric carcinoma and its clinical significance.Acta Histochem 2006;108:19-24[PMID:16530813 DOI:10.1016/j.acthis.2006.01.003]
    189 Gu L,Chen M,Guo D,Zhu H,Zhang W,Pan J,Zhong X,Li X,Qian H,Wang X.PD-L1 and gastric cancer prognosis:A systematic review and meta-analysis.PLo S One 2017;12:e0182692[PMID:28796808 DOI:10.1371/journal.pone.0182692]
    190 Parsa AT,Waldron JS,Panner A,Crane CA,Parney IF,Barry JJ,Cachola KE,Murray JC,Tihan T,Jensen MC,Mischel PS,Stokoe D,Pieper RO.Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma.Nat Med 2007;13:84-88[PMID:17159987 DOI:10.1038/nm1517]
    191 Marzec M,Zhang Q,Goradia A,Raghunath PN,Liu X,Paessler M,Wang HY,Wysocka M,Cheng M,Ruggeri BA,Wasik MA.Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274(PD-L1,B7-H1).Proc Natl Acad Sci U S A 2008;105:20852-20857[PMID:19088198 DOI:10.1073/pnas.0810958105]
    192 Chen L,Gibbons DL,Goswami S,Cortez MA,Ahn YH,Byers LA,Zhang X,Yi X,Dwyer D,Lin W,Diao L,Wang J,Roybal J,Patel M,Ungewiss C,Peng D,Antonia S,Mediavilla-Varela M,Robertson G,Suraokar M,Welsh JW,Erez B,Wistuba II,Chen L,Peng D,Wang S,Ullrich SE,Heymach JV,Kurie JM,Qin FX.Metastasis is regulated via micro RNA-200/ZEB1 axis control of tumour cell PD-L1expression and intratumoral immunosuppression.Nat Commun2014;5:5241[PMID:25348003 DOI:10.1038/ncomms6241]
    193 Mimura K,Teh JL,Okayama H,Shiraishi K,Kua LF,Koh V,Smoot DT,Ashktorab H,Oike T,Suzuki Y,Fazreen Z,Asuncion BR,Shabbir A,Yong WP,So J,Soong R,Kono K.PD-L1 expression is mainly regulated by interferon gamma associated with JAK-STATpathway in gastric cancer.Cancer Sci 2018;109:43-53[PMID:29034543 DOI:10.1111/cas.13424]
    194 B?ger C,Behrens HM,Mathiak M,Krüger S,Kalthoff H,R?cken C.PD-L1 is an independent prognostic predictor in gastric cancer of Western patients.Oncotarget 2016;7:24269-24283[PMID:27009855 DOI:10.18632/oncotarget.8169]
    195 Kim JW,Nam KH,Ahn SH,Park DJ,Kim HH,Kim SH,Chang H,Lee JO,Kim YJ,Lee HS,Kim JH,Bang SM,Lee JS,Lee KW.Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer.Gastric Cancer 2016;19:42-52[PMID:25424150 DOI:10.1007/s10120-014-0440-5]
    196 Chang H,Jung WY,Kang Y,Lee H,Kim A,Kim HK,Shin BK,Kim BH.Programmed death-ligand 1 expression in gastric adenocarcinoma is a poor prognostic factor in a high CD8+tumor infiltrating lymphocytes group.Oncotarget 2016;7:80426-80434[PMID:27741514 DOI:10.18632/oncotarget.12603]
    197 Sun J,Xu K,Wu C,Wang Y,Hu Y,Zhu Y,Chen Y,Shi Q,Yu G,Zhang X.PD-L1 expression analysis in gastric carcinoma tissue and blocking of tumor-associated PD-L1 signaling by two functional monoclonal antibodies.Tissue Antigens 2007;69:19-27[PMID:17212704 DOI:10.1111/j.1399-0039.2006.00701.x]
    198 Schl??er HA,Drebber U,Kloth M,Thelen M,Rothschild SI,Haase S,Garcia-Marquez M,Wennhold K,Berlth F,Urbanski A,Alakus H,Schauss A,Shimabukuro-Vornhagen A,Theurich S,Warnecke-Ebertz U,Stippel DL,Zippelius A,Büttner R,Hallek M,H?lscher AH,Zander T,M?nig SP,von Bergwelt-Baildon M.Immune checkpoints programmed death 1 ligand 1 and cytotoxic T lymphocyte associated molecule 4 in gastric adenocarcinoma.Oncoimmunology 2015;5:e1100789[PMID:27467911 DOI:10.1080/2162402X.2015.1100789]
    199 Kawazoe A,Kuwata T,Kuboki Y,Shitara K,Nagatsuma AK,Aizawa M,Yoshino T,Doi T,Ohtsu A,Ochiai A.Clinicopathological features of programmed death ligand 1 expression with tumorinfiltrating lymphocyte,mismatch repair,and Epstein-Barr virus status in a large cohort of gastric cancer patients.Gastric Cancer 2017;20:407-415[PMID:27629881 DOI:10.1007/s10120-016-0631-3]
    200 Wu P,Wu D,Li L,Chai Y,Huang J.PD-L1 and Survival in Solid Tumors:A Meta-Analysis.PLo S One 2015;10:e0131403[PMID:26114883 DOI:10.1371/journal.pone.0131403]
    201 Xu F,Feng G,Zhao H,Liu F,Xu L,Wang Q,An G.Clinicopathologic Significance and Prognostic Value of B7 Homolog1 in Gastric Cancer:A Systematic Review and Meta-Analysis.Medicine(Baltimore)2015;94:e1911[PMID:26512615 DOI:10.1097/MD.0000000000001911]
    202 Liu YX,Wang XS,Wang YF,Hu XC,Yan JQ,Zhang YL,Wang W,Yang RJ,Feng YY,Gao SG,Feng XS.Prognostic significance of PD-L1 expression in patients with gastric cancer in East Asia:a meta-analysis.Onco Targets Ther 2016;9:2649-2654[PMID:27226727 DOI:10.2147/OTT.S102616]
    203 Zhang M,Dong Y,Liu H,Wang Y,Zhao S,Xuan Q,Wang Y,Zhang Q.The clinicopathological and prognostic significance of PD-L1expression in gastric cancer:a meta-analysis of 10 studies with 1,901patients.Sci Rep 2016;6:37933[PMID:27892511 DOI:10.1038/srep37933]
    204 Fang W,Chen Y,Sheng J,Zhou T,Zhang Y,Zhan J,Liu L,Huang J,Peng P,Zhang L.Association between PD-L1 Expression on Tumour-Infiltrating Lymphocytes and Overall Survival in Patients with Gastric Cancer.J Cancer 2017;8:1579-1585[PMID:28775777 DOI:10.7150/jca.18729]
    205 Gao Y,Li S,Xu D,Chen S,Cai Y,Jiang W,Zhang X,Sun J,Wang K,Chang B,Wang F,Hong M.Prognostic value of programmed death-1,programmed death-ligand 1,programmed death-ligand2 expression,and CD8(+)T cell density in primary tumors and metastatic lymph nodes from patients with stage T1-4N+M0 gastric adenocarcinoma.Chin J Cancer 2017;36:61[PMID:28754154DOI:10.1186/s40880-017-0226-3]
    206 Ma C,Patel K,Singhi AD,Ren B,Zhu B,Shaikh F,Sun W.Programmed Death-Ligand 1 Expression Is Common in Gastric Cancer Associated With Epstein-Barr Virus or Microsatellite Instability.Am J Surg Pathol 2016;40:1496-1506[PMID:27465786 DOI:10.1097/PAS.0000000000000698]
    207 Budczies J,Denkert C,Gy?rffy B,Schirmacher P,Stenzinger A.Chromosome 9p copy number gains involving PD-L1 are associated with a specific proliferation and immune-modulating gene expression program active across major cancer types.BMC Med Genomics2017;10:74[PMID:29212506 DOI:10.1186/s12920-017-0308-8]
    208 Ronan JK.Immunotherapy for Esophageal and Gastric Cancer.ASCO EDUCATIONAL BOOK|asco.org/edbook.2017:292-300
    209 Spranger S,Gajewski TF.Tumor-intrinsic oncogene pathways mediating immune avoidance.Oncoimmunology 2015;5:e1086862[PMID:27141343 DOI:10.1080/2162402X.2015.1086862]
    210 Gajewski TF.The Next Hurdle in Cancer Immunotherapy:Overcoming the Non-T-Cell-Inflamed Tumor Microenvironment.Semin Oncol 2015;42:663-671[PMID:26320069 DOI:10.1053/j.seminoncol.2015.05.011]
    211 Tran PN,Sarkissian S,Chao J,Klempner SJ.PD-1 and PD-L1 as emerging therapeutic targets in gastric cancer:current evidence.Gastrointest Cancer 2017;7:1-11[PMID:28757801 DOI:10.2147/GICTT.S113525]
    212 Reck M,Rodríguez-Abreu D,Robinson AG,Hui R,Cs?szi T,Fül?p A,Gottfried M,Peled N,Tafreshi A,Cuffe S,O’Brien M,Rao S,Hotta K,Leiby MA,Lubiniecki GM,Shentu Y,Rangwala R,Brahmer JR;KEYNOTE-024 Investigators.Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer.NEngl J Med 2016;375:1823-1833[PMID:27718847 DOI:10.1056/NEJMoa1606774]
    213 Taube JM,Klein A,Brahmer JR,Xu H,Pan X,Kim JH,Chen L,Pardoll DM,Topalian SL,Anders RA.Association of PD-1,PD-1ligands,and other features of the tumor immune microenvironment with response to anti-PD-1 therapy.Clin Cancer Res 2014;20:5064-5074[PMID:24714771 DOI:10.1158/1078-0432.CCR-13-3271]
    214 Jiang Y,Zhang Q,Hu Y,Li T,Yu J,Zhao L,Ye G,Deng H,Mou T,Cai S,Zhou Z,Liu H,Chen G,Li G,Qi X.Immuno Score Signature:A Prognostic and Predictive Tool in Gastric Cancer.Ann Surg 2018;267:504-513[PMID:28002059 DOI:10.1097/SLA.0000000000002116]
    215 Lin SJ,Gagnon-Bartsch JA,Tan IB,Earle S,Ruff L,Pettinger K,Ylstra B,van Grieken N,Rha SY,Chung HC,Lee JS,Cheong JH,Noh SH,Aoyama T,Miyagi Y,Tsuburaya A,Yoshikawa T,Ajani JA,Boussioutas A,Yeoh KG,Yong WP,So J,Lee J,Kang WK,Kim S,Kameda Y,Arai T,Zur Hausen A,Speed TP,Grabsch HI,Tan P.Signatures of tumour immunity distinguish Asian and nonAsian gastric adenocarcinomas.Gut 2015;64:1721-1731[PMID:25385008 DOI:10.1136/gutjnl-2014-308252]
    216 Ralph C,Elkord E,Burt DJ,O’Dwyer JF,Austin EB,Stern PL,Hawkins RE,Thistlethwaite FC.Modulation of lymphocyte regulation for cancer therapy:a phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma.Clin Cancer Res2010;16:1662-1672[PMID:20179239 DOI:10.1158/1078-0432.CCR-09-2870]
    217 Culver ME,Gatesman ML,Mancl EE,Lowe DK.Ipilimumab:a novel treatment for metastatic melanoma.Ann Pharmacother 2011;45:510-519[PMID:21505108 DOI:10.1345/aph.1P651]
    218 Moehler MH,Cho JY,Kim YH,Kim JW,Di Bartolomeo M,Ajani JA,Yamaguchi K,Balogh A,Kong-Sanchez MT,Bang YJ.A randomized,open-label,two-arm phase II trial comparing the efficacy of sequential ipilimumab(ipi)versus best supportive care(BSC)following first-line(1L)chemotherapy in patients with unresectable,locally advanced/metastatic(A/M)gastric or gastroesophageal junction(G/GEJ)cancer.Alexandria:J Clin Oncol 2016;34:abstr 4011
    219 Janjigian YY,Ott PA,Calvo E,Kim JW,Ascierto PA,Sharma P,Peltola KJ,Jaeger D,Evans TRJ,De Braud FG,Chau I,Tschaika M,Harbison CT,Cai W,Bendell JC,Le DT.Nivolumab±ipilimumab in pts with advanced(adv)/metastatic chemotherapy refractory(CTx-R)gastric(G),esophageal(E),or gastroesophageal junction(GEJ)cancer:Check Mate 032 study.J Clin Oncol 2017;35:abstract4014220 Janjigian YY,Adenis A,Aucoin JS,Barone C,Boku N,Chau I,Cleary JM,Feeney K,Franke FA,Moehler M,Roca EL,Schenker M,Li M,Ajani JA.Checkmate 649:a randomized,multicenter,open-label,phase 3 study of nivolumab(Nivo)plus ipilimumab(Ipi)versus oxaliplatin plus fluoropyrimidine in patients(Pts)with previously untreated advanced or metastatic gastric(G)or gastroesophageal junction(GEJ)cancer.J Clin Oncol 2017;35:TPS4132[DOI:10.1200/JCO.2017.35.4_suppl.TPS213]
    221 Kang YK,Satoh T,Ryu MH,Chao Y,Kato K,Chung HC,Chen JS,Muro K,Kang WK,Yoshikawa T,Oh SC,Tamura T,Lee KW,Boku N,Chenet LT.Nivolumab(ONO-4538/BMS-936558)as salvage treatment after second or later-line chemotherapy for advanced gastric or gastro-esophageal junction cancer(AGC):a doubleblinded,randomized,phaseⅢtrial.J Clin Oncol 2017;35:abstr 2
    222 Kang YK,Boku N,Satoh T,Ryu MH,Chao Y,Kato K,Chung HC,Chen JS,Muro K,Kang WK,Yeh KH,Yoshikawa T,Oh SC,Bai LY,Tamura T,Lee KW,Hamamoto Y,Kim JG,Chin K,Oh DY,Minashi K,Cho JY,Tsuda M,Chen LT.Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to,or intolerant of,at least two previous chemotherapy regimens(ONO-4538-12,ATTRACTION-2):a randomised,double-blind,placebo-controlled,phase 3 trial.Lancet 2017;390:2461-2471[PMID:28993052 DOI:10.1016/S0140-6736(17)31827-5]
    223 Charalampakis N,Economopoulou P,Kotsantis I,Tolia M,Schizas D,Liakakos T,Elimova E,Ajani JA,Psyrri A.Medical management of gastric cancer:a 2017 update.Cancer Med 2018;7:123-133[PMID:29239137 DOI:10.1002/cam4.1274]
    224 Emens LA,Middleton G.The interplay of immunotherapy and chemotherapy:harnessing potential synergies.Cancer Immunol Res 2015;3:436-443[PMID:25941355 DOI:10.1158/2326-6066.CIR-15-0064]
    225 Langer CJ,Gadgeel SM,Borghaei H,Papadimitrakopoulou VA,Patnaik A,Powell SF,Gentzler RD,Martins RG,Stevenson JP,Jalal SI,Panwalkar A,Yang JC,Gubens M,Sequist LV,Awad MM,Fiore J,Ge Y,Raftopoulos H,Gandhi L;KEYNOTE-021 investigators.Carboplatin and pemetrexed with or without pembrolizumab for advanced,non-squamous non-small-cell lung cancer:a randomised,phase 2 cohort of the open-label KEYNOTE-021 study.Lancet Oncol 2016;17:1497-1508[PMID:27745820 DOI:10.1016/S1470-2045(16)30498-3]
    226 Fuchs CS,Doi T,Woo-Jun Jang R,Muro K,Satoh T,Machado M.KEYNOTE-059 cohort 1:Efficacy and safety of pembrolizumab(pembro)monotherapy in patients with previously treated advanced gastric cancer.J Clin Oncol 2017;35:4003
    227 Fuchs CS,Doi T,Jang RW,Muro K,Satoh T,Machado M,Sun W,Jalal SI,Shah MA,Metges JP,Garrido M,Golan T,Mandala M,Wainberg ZA,Catenacci DV,Ohtsu A,Shitara K,Geva R,Bleeker J,Ko AH,Ku G,Philip P,Enzinger PC,Bang YJ,Levitan D,Wang J,Rosales M,Dalal RP,Yoon HH.Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer:Phase
    2 Clinical KEYNOTE-059 Trial.JAMA Oncol 2018;4:e180013[PMID:29543932 DOI:10.1001/jamaoncol.2018.0013]
    228 Fuchs CS,Ohtsu A,Tabernero J,Van Cutsem E,Wang JD,Lam B,Dalal R,Koshiji M,Banget YJ.Preliminary safety data from KEYNOTE-059:pembrolizumab plus 5-fluorouracil(5-FU)and cisplatin for first-line treatment of advanced gastric cancer.J Clin Oncol 2016;34:abstr 4037
    229 Bang YJ,Muro K,Fuchs CS,Golan T,Geva R,Hara H,Jalal SA,Borg C,Doi T,Wainberg ZA,Wang J,Koshiji M,Dalal RP,Chung HC.KEYNOTE-059 cohort 2:safety and efficacy of pembrolizumab(pembro)plus 5-fluorouracil(5-FU)and cisplatin for first-line(1L)treatment of advanced gastric cancer.J Clin Oncol 2017;35:4012
    230 Doi TP,Piha-Paul SA,Jalal SI,Mai-Dang H,Saraf S,Koshiji M,Csiki I,Bennouna J.Updated results for the advanced esophageal carcinoma cohort of the phase Ib KEYNOTE-028 study of pembrolizumab(MK-3475).J Clin Oncol 2016;34:abstr 7[DOI:10.1200/jco.2016.34.4_suppl.7]
    231 Merck Sharp&Dohme Corp.Study of Pembrolizumab(MK-3475)in Previously-Treated Participants With Advanced Carcinoma of the Esophagus or Esophagogastric Junction(MK-3475-180/KEYNOTE-180).[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:https://clinicaltrials.gov/ct2/show/NCT02559687?term=NCT02559687rank=1 Clinical Trials.gov Identifier:NCT02559687
    232 Ohtsu A,Tabernero J,Bang YJ,Fuchs CS,Sun L,Wang Z,Csiki I,Koshiji M,Van Cutsem E.Pembrolizumab(MK-3475)versus paclitaxel as second-line therapy for advanced gastric or gastroesophageal junction(GEJ)adenocarcinoma:phase 3KEYNOTE-061 study.J Clin Oncol 2016;34:abstr TPS183[DOI:10.1200/jco.2016.34.4_suppl.tps183]
    233 Fuchs CS,Ozguroglu M,Bang YJ,Di Bartolomeo M,Mandala M,Ryu MH,Fornaro L,Olesiński T,Caglevic C,Chung HC,Muro K,Goekkurt E,Mansoor W,Mc Dermott RS,Shacham-Shmueli E,Chen X,Kang SP,Mayo CA,Ohtsu A,Shitara K.Pembrolizumab(pembro)vs paclitaxel(PTX)for previously treated advanced gastric or gastroesophageal junction(G/GEJ)cancer:Phase 3KEYNOTE-061 trial.J Clin Oncol 2018;36:abstr 4062
    234 Merck Sharp Dohme Corp.Study of Pembrolizumab(MK-3475)as First-Line Monotherapy and Combination Therapy for Treatment of Advanced Gastric or Gastroesophageal Junction Adenocarcinoma(MK-3475-062/KEYNOTE-062).[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:https://clinicaltrials.gov/ct2/show/NCT02494583?term=NCT02494583rank=1 Clinical Trials.gov Identifier:NCT02494583
    235 Merck Sharp Dohme Corp.Study of Pembrolizumab(MK-3475)Versus Investigator’s Choice Standard Therapy for Participants With Advanced Esophageal/Esophagogastric Junction Carcinoma That Progressed After First-Line Therapy(MK-3475-181/KEYNOTE-181).[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:https://clinicaltrials.gov/ct2/show/NCT02564263?term=NCT02564263rank=1 Clinical Trials.gov Identifier:NCT02564263
    236 Chung HC,Arkenau H-T,Wyrwicz L,Oh DY,Lee KW,Infante JR,Lee SS,Lee J,Keilholz U,Mita AC,Plummer ER,Kemeny M,Melichar B,Smith DM,Chin KM,von Heydebreck A,Cuillerot JM,Kang YK,Safranet H.Avelumab(MSB0010718C;anti-PD-L1)in patients with advanced gastric or gastroesophageal junction cancer from JAVELIN solid tumor phase Ib trial:analysis of safety and clinical activity.J Clin Oncol 2016;34:abstr 4009
    237 Nishina T,Shitara K,Iwasa S,Hironaka S,Muro K,Esaki T,Satoh T,Yamaguchi T,Machida N,von Heydebreck A,Watanabe M,Doi T.Safety,PD-L1 expression,and clinical activity of avelumab(MSB0010718C),an anti-PD-L1 antibody,in Japanese patients with advanced gastric or gastroesophageal junction cancer.J Clin Oncol2016;34:abstr 168[DOI:10.1200/jco.2016.34.4_suppl.168]
    238 Moehler MH,Ta?eb J,Gurtler JS,Xiong H,Zhang J,Cuillerot JM,Bokuet N.Maintenance therapy with avelumab(MSB0010718C;anti-PD-L1)vs continuation of first-line chemotherapy in patients with unresectable,locally advanced or metastatic gastric cancer:the phase 3 JAVELIN Gastric 100 trial.J Clin Oncol 2016;34:TPS4134)
    239 Segal NH,Antonia SJ,Brahmer JR,Maio M,Blake-Haskins A,Li X.,Khleif S.Preliminary data from a multi-arm expansion study of MEDI4736,an anti-PD-L1 antibody.J Clin Oncol 2014;32:5s
    240 Kelly RJ,Chung,Gu Y,Steele KE,Rebelatto MC,Robbins PB,Almhanna K.(2015).Phase Ib/II study to evaluate the safety and antitumor activity of durvalumab(MEDI4736)and tremelimumab as monotherapy or in combination,in patients with recurrent or metastatic gastric/gastroesophageal junction adenocarcinoma.J Immunotherapy Cancer 2015;32:P157[DOI:10.1186/2051-1426-3-S2-P157]
    241 Pardoll DM.The blockade of immune checkpoints in cancer immunotherapy.Nat Rev Cancer 2012;12:252-264[PMID:22437870 DOI:10.1038/nrc3239]
    242 Bristol-Myers Squibb.An Investigational Immuno-therapy Study of Nivolumab or Placebo in Patients With Resected Esophageal or Gastroesophageal Junction Cancer(Checkmate 577).[accessed2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:https://clinicaltrials.gov/ct2/show/NCT02743494?term=Check Mate-577rank=1Clinical Trials.gov Identifier:NCT02743494
    243 Wada H.Department of Clinical Research in Tumor Immunology,Graduate School of Medicine,Osaka University.Study of Preoperative Combination Therapy With Mogamulizumab and Nivolumab Against Solid Cancer Patients.[accessed 2018 May4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:https://clinicaltrials.gov/ct2/show/NCT02946671?term=NCT02946671rank=1 Clinical Trials.gov Identifier:NCT0294667 Clinical Trials.gov Identifier:NCT02946671
    244 European Organisation for Research and Treatment of CancerEORTC.Postoperative Immunotherapy vs Standard Chemotherapy for Gastric Cancer With High Risk for Recurrence(VESTIGE).[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:https://clinicaltrials.gov/ct2/show/NCT03443856?term=NCT03443856rank=1 Clinical Trials.gov Identifier:NCT03443856
    245 Bristol-Myers Squibb.Ronan K,Johns Hopkins University.Nivolumab or Nivolumab/Ipilimumab Prior to Chemoradiation Plus Nivolumab With II/ⅢGastro/Esophageal Cancer.[accessed2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:https://clinicaltrials.gov/ct2/show/NCT03044613?term=NCT03044613rank=1Clinical Trials.gov Identifier:NCT03044613
    246 Palta M,Duke University.Pembrolizumab,Radiotherapy,and Chemotherapy in Neoadjuvant Treatment of Malignant Esophagogastric Diseases(PROCEED).[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:https://clinicaltrials.gov/ct2/show/NCT03064490?term=NCT03064490cond=gastric+cancerrank=1Clinical Trials.gov Identifier:NCT03064490
    247 Merck Sharp Dohme Corp.Perioperative Chemo and Pembrolizumab in Gastric Cancer.[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:URL:https://clinicaltrials.gov/ct2/show/NCT02918162?term=pembrolizumabcond=gastric+cancerrank=4Clinical Trials.gov Identifier:NCT02918162
    248 Merck Sharp Dohme Corp.Study of Pembrolizumab(MK-3475)Plus Chemotherapy Versus Placebo Plus Chemotherapy in Participants With Gastric or Gastroesophageal Junction(GEJ)Adenocarcinoma(MK-3475-585/KEYNOTE-585).[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:https://clinicaltrials.gov/ct2/show/NCT03221426?term=KEYNOTE-585cond=gastric+cancerrank=1Clinical Trials.gov Identifier:NCT03221426
    249 Merck Sharp Dohme Corp.University of Kansas Medical Center.Perioperative m FOLFOX Plus Pembrolizumab in Gastroesophageal Junction(GEJ)and Stomach Adenocarcinoma.[accessed 2018 May4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:https://clinicaltrials.gov/ct2/show/NCT03488667?term=NCT03488667cond=gastric+cancerrank=1 Clinical Trials.gov Identifier:NCT03488667
    250 Royal Marsden NHS Foundation Trust,Merck Kga A.Study Title:Peri-operative Immuno-Chemotherapy in Operable Oesophageal and Gastric cancer(ICONIC).[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:URL:https://clinicaltrials.gov/ct2/show/NCT03399071?term=NCT03399071cond=gastric+cancerrank=1 Clinical Trials.gov Identifier:NCT03399071
    251 Voron T,Marcheteau E,Pernot S,Colussi O,Tartour E,Taieb J,Terme M.Control of the immune response by pro-angiogenic factors.Front Oncol 2014;4:70[PMID:24765614 DOI:10.3389/fonc.2014.00070]
    252 Dudek AZ,Sica A,Sidani A,Jha GG,Xie H,Alva AS,Stein MN,Singer EA.Phase Ib study of pembrolizumab in combination with bevacizumab for the treatment of metastatic renal cell carcinoma:Big Ten Cancer Research Consortium BTCRC-GU14003.J Clin Oncol 2016;34:suppl.559[DOI:10.1200/jco.2016.34.2_suppl.559]
    253 Solmaz S,Johnstone PA,Forsyth PA.Safety and antitumor activity of hypofractionated stereotactic irradiation(HFSRT)with pembrolizumab(Pembro)and bevacizumab(Bev)in patients(pts)with recurrent high grade gliomas:preliminary results from phase Istudy.J Clin Oncol 2016;34:abstr 2041
    254 Chau I,Calvo E,Santana-Davila R,Ahnert JR,Penel N.Interim safety and clinical activity in patients(pts)with advanced gastric or gastroesophageal junction(G/GEJ)adenocarcinoma from a multicohort phase 1 study of ramucirumab(R)plus pembrolizumab(P).J Clin Oncol 2017;35:abstract 102[DOI:10.1200/JCO.2017.35.4_suppl.102]
    255 Kato K,Department of Gastrointestinal Medical Oncology,National cancer center hospital Japan.A Phase 1/2 Study of Ramucirumab Plus Nivolumab in Participants With Gastric or GEJ Cancer.[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:https://clinicaltrials.gov/ct2/show/NCT02999295?term=NCT02999295con d=gastric+cancerrank=1 Clinical Trials.gov Identifier:NCT02999295
    256 St.Marianna University School of Medicine Hospital,Department of Clinical Oncology.https://upload.umin.ac.jp/cgiopenbin/ctr_e/ctr_view.cgi?recptno=R000029783
    257 New York University School of Medicine,National Cancer Institute(NCI).Lenvatinib Mesylate and Pembrolizumab in Treating Patients With Metastatic or Recurrent Gastric or Gastroesophageal Cancer.[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:URL:https://clinicaltrials.gov/ct2/show/NCT03413397?term=nct03413397cond=gastric+cancerrank=1 Clinical Trials.gov Identifier:NCT03413397
    258 Institut Bergonié,Merck Kga A.A Phase I/II Study of Regorafenib Plus Avelumab in Digestive Tumors(REGOMUNE).[accessed 2018May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:https://clinicaltrials.gov/ct2/show/NCT03475953?term=nct03475953cond=gastric+cancer rank=1 Clinical Trials.gov Identifier:NCT03475953
    259 Vanneman M,Dranoff G.Combining immunotherapy and targeted therapies in cancer treatment.Nat Rev Cancer 2012;12:237-251[PMID:22437869 DOI:10.1038/nrc3237]
    260 Catenacci DV,Kim SS,Gold PJ.A phase 1b/2,open label,dose-escalation study of margetuximab(M)in combination with pembrolizumab(P)in patients with relapsed/refractory advanced HER2+gastroesophageal(GEJ)junction or gastric(G)cancer.JClin Oncol 2017;35:TPS219[DOI:10.1200/JCO.2017.35.4_suppl.TPS219]
    261 Zhai L,Spranger S,Binder DC,Gritsina G,Lauing KL,Giles FJ,Wainwright DA.Molecular Pathways:Targeting IDO1 and Other Tryptophan Dioxygenases for Cancer Immunotherapy.Clin Cancer Res 2015;21:5427-5433[PMID:26519060 DOI:10.1158/1078-0432.CCR-15-0420]
    262 Ott PA,Hodi FS,Kaufman HL,Wigginton JM,Wolchok JD.Combination immunotherapy:a road map.J Immunother Cancer2017;5:16[PMID:28239469 DOI:10.1186/s40425-017-0218-5]
    263 Incyte Corporation.Merck Sharp Dohme Corp.A Phase 1/2 Study Exploring the Safety,Tolerability,and Efficacy of Pembrolizumab(MK-3475)in Combination With Epacadostat(INCB024360)in Subjects With Selected Cancers(INCB 24360-202/MK-3475-037/KEYNOTE-037/ECHO-202).[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:URL:https://clinicaltrials.gov/ct2/show/NCT02178722?term=NCT02178722rank=1 Clinical Trials.gov Identifier:NCT02178722
    264 Kunz P,Stanford University.Epacadostat and Pembrolizumab in Treating Patients With Metastatic or Unresectable Gastroesophageal Junction or Gastric Cancer.In:Clinical Trials.gov[Internet].Bethesda(MD):National Library of Medicine(US).Available from:URL:https://clinicaltrials.gov/ct2/show/NCT03196232?term=nct03196232rank=1
    265 Kidokoro T,Tanikawa C,Furukawa Y,Katagiri T,Nakamura Y,Matsuda K.CDC20,a potential cancer therapeutic target,is negatively regulated by p53.Oncogene 2008;27:1562-1571[PMID:17873905 DOI:10.1038/sj.onc.1210799]
    266 Maire V,Baldeyron C,Richardson M,Tesson B,Vincent-Salomon A,Gravier E,Marty-Prouvost B,De Koning L,Rigaill G,Dumont A,Gentien D,Barillot E,Roman-Roman S,Depil S,Cruzalegui F,PierréA,Tucker GC,Dubois T.TTK/h MPS1 is an attractive therapeutic target for triple-negative breast cancer.PLo S One 2013;8:e63712[PMID:23700430 DOI:10.1371/journal.pone.0063712]
    267 Yim H.Current clinical trials with polo-like kinase 1 inhibitors in solid tumors.Anticancer Drugs 2013;24:999-1006[PMID:23949254 DOI:10.1097/CAD.0000000000000007]
    268 Gray D,Jubb AM,Hogue D,Dowd P,Kljavin N,Yi S,Bai W,Frantz G,Zhang Z,Koeppen H,de Sauvage FJ,Davis DP.Maternal embryonic leucine zipper kinase/murine protein serinethreonine kinase 38 is a promising therapeutic target for multiple cancers.Cancer Res 2005;65:9751-9761[PMID:16266996 DOI:10.1158/0008-5472.CAN-04-4531]
    269 Wang L,Rubinstein R,Lines JL,Wasiuk A,Ahonen C,Guo Y,Lu LF,Gondek D,Wang Y,Fava RA,Fiser A,Almo S,Noelle RJ.VISTA,a novel mouse Ig superfamily ligand that negatively regulates T cell responses.J Exp Med 2011;208:577-592[PMID:21383057 DOI:10.1084/jem.20100619]
    270 Le Mercier I,Chen W,Lines JL,Day M,Li J,Sergent P,Noelle RJ,Wang L.VISTA Regulates the Development of Protective Antitumor Immunity.Cancer Res 2014;74:1933-1944[PMID:24691994 DOI:10.1158/0008-5472.CAN-13-1506]
    271 Liu J,Yuan Y,Chen W,Putra J,Suriawinata AA,Schenk AD,Miller HE,Guleria I,Barth RJ,Huang YH,Wang L.Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses.Proc Natl Acad Sci USA 2015;112:6682-6687[PMID:25964334 DOI:10.1073/pnas.1420370112]
    272 Curis,Inc.A Study of CA-170(Oral PD-L1,PD-L2 and VISTACheckpoint Antagonist)in Patients With Advanced Tumors and Lymphomas.[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:https://clinicaltrials.gov/ct2/show/NCT02812875?term=NCT02812875rank=1 Clinical Trials.gov Identifier:NCT02812875
    273 B?ger C,Behrens HM,Krüger S,R?cken C.The novel negative checkpoint regulator VISTA is expressed in gastric carcinoma and associated with PD-L1/PD-1:A future perspective for a combined gastric cancer therapy?Oncoimmunology 2017;6:e1293215[PMID:28507801 DOI:10.1080/2162402X.2017.1293215]
    274 Gilead Sciences.Andecaliximab Combined With Nivolumab Versus Nivolumab Alone in Adults With Unresectable or Recurrent Gastric or Gastroesophageal Junction Adenocarcinoma.[accessed 2018 May4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:https://clinicaltrials.gov/ct2/show/NCT02864381?term=NCT02864381rank=1 Clinical Trials.gov Identifier:NCT02864381
    275 Aanur P,Gutierrez M,Kelly RJ,Ajani JA,Ku GY,Denlinger CS.FRACTION(fast real-time assessment of combination therapies in immuno-oncology)-gastric cancer(GC):a randomized,open-label,adaptive,phase 2 study of nivolumab in combination with other immuno-oncology(IO)agents in patients with advanced GC.J Clin Oncol 2017;35:TPS4137
    276 Mayo Clinic,National Cancer Institute(NCI).Pembrolizumab,Combination Chemotherapy,and Radiation Therapy Before Surgery in Treating Adult Patients With Locally Advanced Gastroesophageal Junction or Gastric Cardia Cancer That Can Be Removed by Surgery.[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:https://clinicaltrials.gov/ct2/show/NCT02730546?term=NCT02730546rank=1 Clinical Trials.gov Identifier:NCT02730546
    277 Kono K,Fukushima Medical University Hospital.Checkpoint Inhibitor and Radiotherapy for Recurrent Gastric Cancer(CIRCUIT).[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:https://clinicaltrials.gov/ct2/show/NCT03453164?term=NCT03453164rank=1 Clinical Trials.gov Identifier:NCT03453164
    278 L?ubli H,Balmelli C,Bossard M,Pfister O,Glatz K,Zippelius A.Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma.JImmunother Cancer 2015;3:11[PMID:25901283 DOI:10.1186/s40425-015-0057-1]
    279 Johnson DB,Balko JM,Compton ML,Chalkias S,Gorham J,Xu Y,Hicks M,Puzanov I,Alexander MR,Bloomer TL,Becker JR,Slosky DA,Phillips EJ,Pilkinton MA,Craig-Owens L,Kola N,Plautz G,Reshef DS,Deutsch JS,Deering RP,Olenchock BA,Lichtman AH,Roden DM,Seidman CE,Koralnik IJ,Seidman JG,Hoffman RD,Taube JM,Diaz LA Jr,Anders RA,Sosman JA,Moslehi JJ.Fulminant Myocarditis with Combination Immune Checkpoint Blockade.N Engl J Med 2016;375:1749-1755[PMID:27806233 DOI:10.1056/NEJMoa1609214]
    280 Myint ZW,Goel G.Role of modern immunotherapy in gastrointestinal malignancies:a review of current clinical progress.J Hematol Oncol 2017;10:86[PMID:28434400 DOI:10.1186/s13045-017-0454-7]
    281 Yonsei University,Korea.Biomarker-Integrated Umbrella,Advanced Gastric Cancer.[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:https://clinicaltrials.gov/ct2/show/NCT02951091?ter m=NCT02951091rank=1 Clinical Trials.gov Identifier:NCT0295109
    282 National Cancer Institute(NCI).[accessed 2018 May 4].In:Clinical Trials.gov[Internet].Bethesda(MD):U.S.National Library of Medicine.Available from:https://clinicaltrials.gov/ct2/show/NCT02465060?term=NCT02465060rank=1 Clinical Trials.gov Identifier:NCT02465060

© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号

地址:北京市海淀区学院路29号 邮编:100083

电话:办公室:(+86 10)66554848;文献借阅、咨询服务、科技查新:66554700