抗CD47靶向治疗研究现状及应用前景
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摘要
在肿瘤发生发展过程中,肿瘤细胞逃逸了免疫系统的监视;免疫逃逸机制对于研发新的抗肿瘤治疗方案具有重要的意义。免疫治疗旨在激活患者自身的免疫系统,是肿瘤治疗相关研究的前沿,具有广阔的应用前景。CD47是一种广泛表达的细胞表面分子,肿瘤细胞可能借此"别吃我"信号,逃避了肿瘤免疫;肿瘤干细胞中CD47的表达水平甚至比肿瘤细胞更高。通过使用抗CD47抗体阻断CD47-SIRPα通路,从而介导细胞吞噬作用,能够靶向性杀伤肿瘤细胞。现在多项关于CD47靶向治疗的临床试验正在进行中,包括两种单克隆抗体和一种融合蛋白。然而由于使用动物模型不一,可能高估了这些药物的临床疗效预测。现将CD47抗肿瘤治疗相关研究的背景及潜在问题加以综述,并对该治疗的未来应用前景予以展望。
In cancer development and progression, tumor cells escape from the surveillance of our immune system. Understanding the mechanism behind this phenomenon is crucial in developing new anti-cancer therapies. Immunotherapy, which aims to trigger the immune reaction of the patient's own immune system, stands in the spotlight of cancer research and has promising applications. CD47 is ubiquitously expressed in many kinds of cells serving as a "do-not-eat-me" signal. Cancer cells may take advantage of CD47 overexpression to escape from immunosurveillance. Cancer stem cells have high expression levels of CD47. Blocking the interaction between CD47 and SIRPα can induce targeted phagocytosis of cancer cells. Several clinical trials on three different kinds of CD47-targeted drugs are ongoing, but the animal models used may have a potential issue in estimating clinical efficacy. The present study aims to review the development and current status of anti-CD47 anti-cancer therapy, raise the concerns on the animal models, and discuss some perspectives on future clinical applications.
In cancer development and progression, tumor cells escape from the surveillance of our immune system. Understanding the mechanism behind this phenomenon is crucial in developing new anti-cancer therapies. Immunotherapy, which aims to trigger the immune reaction of the patient's own immune system, stands in the spotlight of cancer research and has promising applications. CD47 is ubiquitously expressed in many kinds of cells serving as a "do-not-eat-me" signal. Cancer cells may take advantage of CD47 overexpression to escape from immunosurveillance. Cancer stem cells have high expression levels of CD47. Blocking the interaction between CD47 and SIRPα can induce targeted phagocytosis of cancer cells. Several clinical trials on three different kinds of CD47-targeted drugs are ongoing, but the animal models used may have a potential issue in estimating clinical efficacy. The present study aims to review the development and current status of anti-CD47 anti-cancer therapy, raise the concerns on the animal models, and discuss some perspectives on future clinical applications.
引文
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[3]Gu W,Gerling I,Jiao Y,et al.Candidate genes within known QTL of type1 diabetes from mouse models[J].BMC Bioinformatics,2008,9(S7):P2.
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[6]Chao MP,Alizadeh AA,Tang C,et al.Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma[J].Cell,2010,142(5):699-713.
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[8]Ju BH,Huang YT,Tian J,et al.In vitro application of anti-CD47monoclonal antibody for targeted therapy of ovarian cancer[J].Chinese Journal of Clinical Oncology,2013,40(8):440-443.[鞠宝辉,黄宇婷,田菁,等.抗CD47单克隆抗体对卵巢癌细胞靶向治疗的体外研究[J].中国肿瘤临床,2013,40(8):440-443.]
[9]Weiskopf K,Jahchan NS,Schnorr PJ,et al.CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer[J].J Clin Invest,2016,126(7):2610-2620.
[10]Liu X,Kwon H,Li Z,et al.Is CD47 an innate immune checkpoint for tumor evasion[J].J Hematol Oncol,2017,10(1):12.
[11]Oldenborg PA,Gresham HD,Chen Y,et al.Lethal autoimmune hemolytic anemia in CD47-deficient nonobese diabetic(NOD)mice[J].Blood,2002,99(10):3500-3504.
[12]Oldenborg PA,Zheleznyak A,Fang YF,et al.Role of CD47 as a marker of self on red blood cells[J].Science,2000,288(5473):2051-2054.
[13]Olsson M,Bruhns P,Frazier WA,et al.Platelet homeostasis is regulated by platelet expression of CD47 under normal conditions and in passive immune thrombocytopenia[J].Blood,2005,105(9):3577-3582.
[14]Jaiswal S,Jamieson CH,Pang WW,et al.CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis[J].Cell,2009,138(2):271-285.
[15]Majeti R,Chao MP,Alizadeh AA,et al.CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells[J].Cell,2009,138(2):286-299.
[16]Huang Y,Ju B,Tian J,et al.Ovarian cancer stem cell-specific gene expression profiling and targeted drug prescreening[J].Oncol Rep,2014,31(3):1235-1248.
[17]Hu L,Ru K,Zhang L,et al.Fluorescence in situ hybridization(FISH):an increasingly demanded tool for biomarker research and personalized medicine[J].Biomarker Research,2014,2(3).doi:10.1186/2050-7771-2-3.
[18]Huang YT,Hu LP,Tian J,et al.c-myc amplification and Rb1 deletion in epithelial ovarian cancer[J].Chinese Journal of Clinical Oncology,2011;39(20):1547-1551.[黄宇婷,胡林萍,田菁,等.上皮性卵巢癌中c-myc基因扩增和Rb1基因缺失及临床意义[J].中国肿瘤临床,2011,39(20):1547-1551.]
[19]Huang YT,Hu LP,Ju BH,et al.Establishing the quantitative multi-gene fluorescence in situ hybridization technique in ovarian cancer research[J].Progress in Obstetrics and Gynecology,2013,22(2):86-89.[黄宇婷,胡林萍,鞠宝辉,等.定量多基因荧光原位杂交技术在卵巢癌研究中的初步探索[J].现代妇产科进展,2013,22(2):86-89.]
[20]Ju BH,Tian J,Huang YT,et al.Analysis of shared characteristics of ovarian cancer stem cell by gene expression profiling[J].Shandong Medicine,2013,53(24):1-5.[鞠宝辉,田菁,黄宇婷,等.卵巢癌干细胞基因表达谱共有特征分析[J].山东医药,2013,53(24):1-5.]
[21]Huang YT,Zhao L,Fu Z,et al.Therapeutic effects of tyroservatide on metastasis of lung cancer and its mechanism affecting integrin-focal adhesion kinase signal transduction[J].Drug Des Devel Ther,2016,10:649-663.
[22]Huang YT ZM,Xu HX,et al.RASAL2 down-regulation in ovarian cancer promotes epithelial-mesenchymal transition and metastasis[J].Oncotarget,2014,5(16):6734-6745.
[23]Zhao XW,van Beek EM,Schornagel K,et al.CD47-signal regulatory protein-alpha(SIRPαlpha)interactions form a barrier for antibodymediated tumor cell destruction[J].Proc Nat Acad Sci U S A,2011,108(45):18342-18347.
[24]Chao MP,Tang C,Pachynski RK,et al.Extranodal dissemination of nonHodgkin lymphoma requires CD47 and is inhibited by anti-CD47 antibody therapy[J].Blood,2011,118(18):4890-4901.
[25]Kwong LS,Brown MH,Barclay AN,et al.Signal-regulatory proteinαfrom the NOD mouse binds human CD47 with an exceptionally high affinity-implications for engraftment of human cells[J].Immunology,2014,143(1):61-67.
[26]Sockolosky JT,Dougan M,Ingram JR,et al.Durable antitumor responses to CD47 blockade require adaptive immune stimulation[J].Proc Nat Acad Sci U S A,2016,113(19):E2646-E2654.
[27]Liu X,Pu Y,Cron K,et al.CD47 blockade triggers T cell-mediated destruction of immunogenic tumors[J].Nat Med,2015,21(10):1209-1215.
[28]Willingham SB,Volkmer JP,Weiskopf K,et al.Reply to Soto-Pantoja et al.and Zhao et al.Targeting CD47 on human solid tumors[J].Proc Nat Acad Sci U S A,2012,109(42):E2844-E2845.
[29]Strowig T,Rongvaux A,Rathinam C,et al.Transgenic expression of human signal regulatory protein alpha in Rag2-/-γc-/-mice improves engraftment of human hematopoietic cells in humanized mice[J].Proc Nat Acad Sci U S A,2011,108(32):13218-13223.
[30]Rongvaux A,Willinger T,Martinek J,et al.Development and function of human innate immune cells in a humanized mouse model[J].Nat Biotechnol,2014,32(4):364-372.
[31]Stecklum M,Wulf-Goldenberg A,Brzezicha B,et al.Abstract B126:Correlation of tumor growth inhibition by check point inhibitors with PD-L1 expression in preclinical patient derived xenograft(PDX)models[J].Cancer Immunology Research,2016,4(11 Suppl):B126-B.
[32]Lv Z,Bian Z,Shi L,et al.Loss of Cell Surface CD47 Clustering Formation and Binding Avidity to SIRPαFacilitate Apoptotic Cell Clearance by Macrophages[J].J Immunol,2015,195(2):661-671.
[33]Subramanian S,Boder ET,Discher DE.Phylogenetic Divergence of CD47Interactions with Human Signal Regulatory ProteinαReveals Locus of Species Specificity IMPLICATIONS FOR THE BINDING SITE[J].J Bio Chem,2007,282(3):1805-1818.
[34]Weiskopf K,Ring AM,Ho CCM,et al.Engineered SIRPαvariants as immunotherapeutic adjuvants to anticancer antibodies[J].Science,2013,341(6141):88-91.
[35]Subramanian S,Parthasarathy R,Sen S,et al.Species-and cell typespecific interactions between CD47 and human SIRPα[J].Blood,2006,107(6):2548-2556.
[36]Weiskopf K,Ring AM,Guo N,et al.Direct SIRPαBlockade Augments Macrophage Responses to Therapeutic Anticancer Antibodies[J].Blood,2014,124(21):2729.
[37]Chao MP,Jaiswal S,Weissman-Tsukamoto R,et al.Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47[J].Sci Transl Med,2010,2(63):63ra94.
[38]Feng M,Chen JY,Weissman-Tsukamoto R,et al.Macrophages eat cancer cells using their own calreticulin as a guide:roles of TLR and Btk[J].Proc Nat Acad Sci U S A,2015,112(7):2145-2150.
[39]Li SS,Forsl?w A,Sundqvist KG.Autocrine regulation of T cell motility by calreticulin-thrombospondin-1 interaction[J].J Immunol,2005,174(2):654-661.
[40]Sikic BI,Narayanan S,Colevas AD,et al.A first-in-human,first-in-class phase I trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers[J].J Clin Oncol,2016,34(suppl):abstr3019..
[41]Ansell S,Chen RW,Flinn IW,et al.A Phase 1 Study of TTI-621,a Novel Immune Checkpoint Inhibitor Targeting CD47,in Patients with Relapsed or Refractory Hematologic Malignancies[J].Blood,2016,128(22):1812.
[42]Petrova PS,Viller NN,Wong M,et al.TTI-621(SIRPαFc):A CD47-Blocking Innate Immune Checkpoint Inhibitor with Broad Anti-Tumor Activity and Minimal Erythrocyte Binding[M].Clinical Cancer Research,2017.
[43]Huang YT,Cheng MJ,Xu CJ,Stem cell theory of endometriosis etiology,Journal of Jiangsu University(Medicine Edition),2008,18(5):451-454.[黄宇婷,程明军,徐丛剑.子宫内膜异位症病因的干细胞学说[J].江苏大学学报(医学版),2008,18(5):451-454.
[44]Huang YT,Zhang WB,Cheng MJ,et al.Stem cell and endometriosis[J].International Journal of Gynecology&Obstetrics,2009,36(4):299-302.[黄宇婷,张雯碧,程明军,等.干细胞与子宫内膜异位症[J].国际妇产科学杂志,2009,36(4):299-302.]
[45]Xu CJ,Cheng MJ,Huang YT,et al.Advances in etiology of endometriosis,Chinese Journal of Practical Gynecology and Obstetrics,2009,25(9):712-714.[徐丛剑,程明军,黄宇婷,等,子宫内膜异位症病因学研究进展[J].中国实用妇科与产科杂志,2009,25(9):712-714.]
[46]Zhang WB,Cheng MJ,Huang YT,et al.A study in vitro on differentiation of bone marrow mesenchymal stem cells into endometrial epithelial cells in mice[J].Eur J Obstel Gynecol Reprod Biol,2012,160(2):185-190.
[47]Huang YT,Ma Y,Gao P,et al.Targeting CD47:the achievements and concerns of current studies on cancer immunotherapy[J].J Thorac Dis,2017,9(2):E168-E174.
[2]Gao P,Jiao Y,Xiong Q,et al.Genetic and molecular basis of QTL of diabetes in mouse:genes and polymorphisms[J].Current genomics,2008,9(5):324-337.
[3]Gu W,Gerling I,Jiao Y,et al.Candidate genes within known QTL of type1 diabetes from mouse models[J].BMC Bioinformatics,2008,9(S7):P2.
[4]Chen DS,Mellman I.Oncology meets immunology:the cancer-immunity cycle[J].Immunity,2013,39(1):1-10.
[5]Huang,YT.Hao Q.CD47-A novel target in ovarian cancer treatment[J]?Journal of Jiangsu University(Medicine Edition),2011,21(3):273-276.[黄宇婷,郝权.CD47_卵巢癌治疗的新靶点[J]?江苏大学学报(医学版),2011,21(3):273-276.]
[6]Chao MP,Alizadeh AA,Tang C,et al.Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma[J].Cell,2010,142(5):699-713.
[7]Willingham SB,Volkmer JP,Gentles AJ,et al.The CD47-signal regulatory protein alpha(SIRPα)interaction is a therapeutic target for human solid tumors[J].Proc Nat Acad Sci U S A,2012,109(17):6662-6667.
[8]Ju BH,Huang YT,Tian J,et al.In vitro application of anti-CD47monoclonal antibody for targeted therapy of ovarian cancer[J].Chinese Journal of Clinical Oncology,2013,40(8):440-443.[鞠宝辉,黄宇婷,田菁,等.抗CD47单克隆抗体对卵巢癌细胞靶向治疗的体外研究[J].中国肿瘤临床,2013,40(8):440-443.]
[9]Weiskopf K,Jahchan NS,Schnorr PJ,et al.CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer[J].J Clin Invest,2016,126(7):2610-2620.
[10]Liu X,Kwon H,Li Z,et al.Is CD47 an innate immune checkpoint for tumor evasion[J].J Hematol Oncol,2017,10(1):12.
[11]Oldenborg PA,Gresham HD,Chen Y,et al.Lethal autoimmune hemolytic anemia in CD47-deficient nonobese diabetic(NOD)mice[J].Blood,2002,99(10):3500-3504.
[12]Oldenborg PA,Zheleznyak A,Fang YF,et al.Role of CD47 as a marker of self on red blood cells[J].Science,2000,288(5473):2051-2054.
[13]Olsson M,Bruhns P,Frazier WA,et al.Platelet homeostasis is regulated by platelet expression of CD47 under normal conditions and in passive immune thrombocytopenia[J].Blood,2005,105(9):3577-3582.
[14]Jaiswal S,Jamieson CH,Pang WW,et al.CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis[J].Cell,2009,138(2):271-285.
[15]Majeti R,Chao MP,Alizadeh AA,et al.CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells[J].Cell,2009,138(2):286-299.
[16]Huang Y,Ju B,Tian J,et al.Ovarian cancer stem cell-specific gene expression profiling and targeted drug prescreening[J].Oncol Rep,2014,31(3):1235-1248.
[17]Hu L,Ru K,Zhang L,et al.Fluorescence in situ hybridization(FISH):an increasingly demanded tool for biomarker research and personalized medicine[J].Biomarker Research,2014,2(3).doi:10.1186/2050-7771-2-3.
[18]Huang YT,Hu LP,Tian J,et al.c-myc amplification and Rb1 deletion in epithelial ovarian cancer[J].Chinese Journal of Clinical Oncology,2011;39(20):1547-1551.[黄宇婷,胡林萍,田菁,等.上皮性卵巢癌中c-myc基因扩增和Rb1基因缺失及临床意义[J].中国肿瘤临床,2011,39(20):1547-1551.]
[19]Huang YT,Hu LP,Ju BH,et al.Establishing the quantitative multi-gene fluorescence in situ hybridization technique in ovarian cancer research[J].Progress in Obstetrics and Gynecology,2013,22(2):86-89.[黄宇婷,胡林萍,鞠宝辉,等.定量多基因荧光原位杂交技术在卵巢癌研究中的初步探索[J].现代妇产科进展,2013,22(2):86-89.]
[20]Ju BH,Tian J,Huang YT,et al.Analysis of shared characteristics of ovarian cancer stem cell by gene expression profiling[J].Shandong Medicine,2013,53(24):1-5.[鞠宝辉,田菁,黄宇婷,等.卵巢癌干细胞基因表达谱共有特征分析[J].山东医药,2013,53(24):1-5.]
[21]Huang YT,Zhao L,Fu Z,et al.Therapeutic effects of tyroservatide on metastasis of lung cancer and its mechanism affecting integrin-focal adhesion kinase signal transduction[J].Drug Des Devel Ther,2016,10:649-663.
[22]Huang YT ZM,Xu HX,et al.RASAL2 down-regulation in ovarian cancer promotes epithelial-mesenchymal transition and metastasis[J].Oncotarget,2014,5(16):6734-6745.
[23]Zhao XW,van Beek EM,Schornagel K,et al.CD47-signal regulatory protein-alpha(SIRPαlpha)interactions form a barrier for antibodymediated tumor cell destruction[J].Proc Nat Acad Sci U S A,2011,108(45):18342-18347.
[24]Chao MP,Tang C,Pachynski RK,et al.Extranodal dissemination of nonHodgkin lymphoma requires CD47 and is inhibited by anti-CD47 antibody therapy[J].Blood,2011,118(18):4890-4901.
[25]Kwong LS,Brown MH,Barclay AN,et al.Signal-regulatory proteinαfrom the NOD mouse binds human CD47 with an exceptionally high affinity-implications for engraftment of human cells[J].Immunology,2014,143(1):61-67.
[26]Sockolosky JT,Dougan M,Ingram JR,et al.Durable antitumor responses to CD47 blockade require adaptive immune stimulation[J].Proc Nat Acad Sci U S A,2016,113(19):E2646-E2654.
[27]Liu X,Pu Y,Cron K,et al.CD47 blockade triggers T cell-mediated destruction of immunogenic tumors[J].Nat Med,2015,21(10):1209-1215.
[28]Willingham SB,Volkmer JP,Weiskopf K,et al.Reply to Soto-Pantoja et al.and Zhao et al.Targeting CD47 on human solid tumors[J].Proc Nat Acad Sci U S A,2012,109(42):E2844-E2845.
[29]Strowig T,Rongvaux A,Rathinam C,et al.Transgenic expression of human signal regulatory protein alpha in Rag2-/-γc-/-mice improves engraftment of human hematopoietic cells in humanized mice[J].Proc Nat Acad Sci U S A,2011,108(32):13218-13223.
[30]Rongvaux A,Willinger T,Martinek J,et al.Development and function of human innate immune cells in a humanized mouse model[J].Nat Biotechnol,2014,32(4):364-372.
[31]Stecklum M,Wulf-Goldenberg A,Brzezicha B,et al.Abstract B126:Correlation of tumor growth inhibition by check point inhibitors with PD-L1 expression in preclinical patient derived xenograft(PDX)models[J].Cancer Immunology Research,2016,4(11 Suppl):B126-B.
[32]Lv Z,Bian Z,Shi L,et al.Loss of Cell Surface CD47 Clustering Formation and Binding Avidity to SIRPαFacilitate Apoptotic Cell Clearance by Macrophages[J].J Immunol,2015,195(2):661-671.
[33]Subramanian S,Boder ET,Discher DE.Phylogenetic Divergence of CD47Interactions with Human Signal Regulatory ProteinαReveals Locus of Species Specificity IMPLICATIONS FOR THE BINDING SITE[J].J Bio Chem,2007,282(3):1805-1818.
[34]Weiskopf K,Ring AM,Ho CCM,et al.Engineered SIRPαvariants as immunotherapeutic adjuvants to anticancer antibodies[J].Science,2013,341(6141):88-91.
[35]Subramanian S,Parthasarathy R,Sen S,et al.Species-and cell typespecific interactions between CD47 and human SIRPα[J].Blood,2006,107(6):2548-2556.
[36]Weiskopf K,Ring AM,Guo N,et al.Direct SIRPαBlockade Augments Macrophage Responses to Therapeutic Anticancer Antibodies[J].Blood,2014,124(21):2729.
[37]Chao MP,Jaiswal S,Weissman-Tsukamoto R,et al.Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47[J].Sci Transl Med,2010,2(63):63ra94.
[38]Feng M,Chen JY,Weissman-Tsukamoto R,et al.Macrophages eat cancer cells using their own calreticulin as a guide:roles of TLR and Btk[J].Proc Nat Acad Sci U S A,2015,112(7):2145-2150.
[39]Li SS,Forsl?w A,Sundqvist KG.Autocrine regulation of T cell motility by calreticulin-thrombospondin-1 interaction[J].J Immunol,2005,174(2):654-661.
[40]Sikic BI,Narayanan S,Colevas AD,et al.A first-in-human,first-in-class phase I trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers[J].J Clin Oncol,2016,34(suppl):abstr3019..
[41]Ansell S,Chen RW,Flinn IW,et al.A Phase 1 Study of TTI-621,a Novel Immune Checkpoint Inhibitor Targeting CD47,in Patients with Relapsed or Refractory Hematologic Malignancies[J].Blood,2016,128(22):1812.
[42]Petrova PS,Viller NN,Wong M,et al.TTI-621(SIRPαFc):A CD47-Blocking Innate Immune Checkpoint Inhibitor with Broad Anti-Tumor Activity and Minimal Erythrocyte Binding[M].Clinical Cancer Research,2017.
[43]Huang YT,Cheng MJ,Xu CJ,Stem cell theory of endometriosis etiology,Journal of Jiangsu University(Medicine Edition),2008,18(5):451-454.[黄宇婷,程明军,徐丛剑.子宫内膜异位症病因的干细胞学说[J].江苏大学学报(医学版),2008,18(5):451-454.
[44]Huang YT,Zhang WB,Cheng MJ,et al.Stem cell and endometriosis[J].International Journal of Gynecology&Obstetrics,2009,36(4):299-302.[黄宇婷,张雯碧,程明军,等.干细胞与子宫内膜异位症[J].国际妇产科学杂志,2009,36(4):299-302.]
[45]Xu CJ,Cheng MJ,Huang YT,et al.Advances in etiology of endometriosis,Chinese Journal of Practical Gynecology and Obstetrics,2009,25(9):712-714.[徐丛剑,程明军,黄宇婷,等,子宫内膜异位症病因学研究进展[J].中国实用妇科与产科杂志,2009,25(9):712-714.]
[46]Zhang WB,Cheng MJ,Huang YT,et al.A study in vitro on differentiation of bone marrow mesenchymal stem cells into endometrial epithelial cells in mice[J].Eur J Obstel Gynecol Reprod Biol,2012,160(2):185-190.
[47]Huang YT,Ma Y,Gao P,et al.Targeting CD47:the achievements and concerns of current studies on cancer immunotherapy[J].J Thorac Dis,2017,9(2):E168-E174.