胰腺导管腺癌的免疫治疗——挑战与机遇并存
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摘要
胰腺导管腺癌(PDAC)是胰腺癌中最常见的一种恶性肿瘤类型,且极易发生微转移。尽管近年来恶性肿瘤的免疫治疗取得重大进步,以程序性细胞死亡蛋白-1/程序性死亡配体-1抗体为代表的免疫检查点阻断,彻底改变了非小细胞肺癌、黑色素瘤、尿路上皮癌和肾癌等的临床诊疗。然而,由于PDAC的低免疫原性和独特的肿瘤微环境(TME),该免疫治疗方案在PDAC中并不尽如人意,PDAC的5年生存率在所有恶性肿瘤中仍为最差。随着对PDAC-TME的研究发展和理解的深入,深度解析免疫系统、肿瘤细胞和基质信号之间高度复杂的相互作用网络,将有助于开发针对PDAC免疫疗法的合理组合。通过阐述PDAC-TME的免疫独特性,探讨PDAC的潜在治疗机会以及相关临床研究进展。
Pancreatic ductal adenocarcinoma( PDAC) is the most common type of pancreatic cancer,and its micrometastases are commonly seen in clinical practice. Although great progress has been made in immunotherapy for malignancies in recent years,immune checkpoint blockade focusing on programmed cell death protein 1( PD-1)/programmed death-ligand 1( PD-L1) has changed the clinical diagnosis and treatment of non-small cell lung cancer,melanoma,urothelial carcinoma,and renal carcinoma. However,the clinical effect of immunotherapy in PDAC is limited by the low immunogenicity and unique tumor microenvironment( TME) of PDAC. With the research advances in PDAC-TME,an in-depth analysis of the highly complex interaction network between immune system,tumor cell,and matrix signal may help to develop a rational combination of immunotherapies for PDAC. By elaborating on the unique immunological features of PDAC-TME,this article reviews the potential treatment opportunities for PDAC and the advances in clinical research.
Pancreatic ductal adenocarcinoma( PDAC) is the most common type of pancreatic cancer,and its micrometastases are commonly seen in clinical practice. Although great progress has been made in immunotherapy for malignancies in recent years,immune checkpoint blockade focusing on programmed cell death protein 1( PD-1)/programmed death-ligand 1( PD-L1) has changed the clinical diagnosis and treatment of non-small cell lung cancer,melanoma,urothelial carcinoma,and renal carcinoma. However,the clinical effect of immunotherapy in PDAC is limited by the low immunogenicity and unique tumor microenvironment( TME) of PDAC. With the research advances in PDAC-TME,an in-depth analysis of the highly complex interaction network between immune system,tumor cell,and matrix signal may help to develop a rational combination of immunotherapies for PDAC. By elaborating on the unique immunological features of PDAC-TME,this article reviews the potential treatment opportunities for PDAC and the advances in clinical research.
引文
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[23] GERLINGER M,ROWAN AJ,HORSWELL S,et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing[J]. N Engl J Med,2012,366(10):883-892.
[24] WANG L,MA Q,CHEN X,et al. Clinical significance of B7-H1 and B7-1 expressions in pancreatic carcinoma[J]. World J Surg,2010,34(5):1059-1065.
[25] CHEN Y,SUN J,ZHAO H,et al. The coexpression and clinical significance of costimulatory molecules B7-H1,B7-H3,and B7-H4 in human pancreatic cancer[J]. Onco Targets Ther,2014,7:1465-1472.
[26] LOOS M,GIESE NA,KLEEFF J,et al. Clinical significance and regulation of the costimulatory molecule B7-H1 in pancreatic cancer[J]. Cancer Lett,2008,268(1):98-109.
[27] GENG L,HUANG D,LIU J,et al. B7-H1 up-regulated expression in human pancreatic carcinoma tissue associates with tumor progression[J]. J Cancer Res Clin Oncol,2008,134(9):1021-1027.
[28] BIRNBAUM DJ,FINETTI P,LOPRESTI A,et al. Prognostic value of PDL1 expression in pancreatic cancer[J]. Oncotarget,2016,7(44):71198-71210.
[29] ZHANG CM,LV JF,GONG L,et al. Role of deficient mismatch repair in the personalized management of colorectal cancer[J]. Int J Environ Res Public Health,2016,13(9):E892.
[30] SHARP JT,LIDSKY MD,DUFFY J,et al. Comparison of two dosage schedules of gold salts in the treatment of rheumatoid arthritis. Relationship of serum gold levels to therapeutic response[J]. Arthritis Rheum,1977,20(6):1179-1187.
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[32] CHAMPIAT S,FERTE C,LEBEL-BINAY S,et al. Exomics and immunogenics:Bridging mutational load and immune checkpoints efficacy[J]. Oncoimmunology,2014,3(1):e27817.
[33] LATSOUDIS H,MASHREGHI MF,GRUN JR,et al. Differential expression of miR-4520a associated with pyrin mutations in familial mediterranean fever(FMF)[J]. J Cell Physiol,2017,232(6):1326-1336.
[34] KIM ST,KLEMPNER SJ,PARK SH,et al. Correlating programmed death ligand 1(PD-L1)expression,mismatch repair deficiency,and outcomes across tumor types:Lmplications for immunotherapy[J]. Oncotarget,2017,8(44):77415-77423.
[35] MARISA L,SVRCEK M,COLLURA A,et al. The balance between cytotoxic T-cell lymphocytes and immune checkpoint expression in the prognosis of colon tumors[J]. J Natl Cancer Inst,2018,110(1):68-77.
[36] WALKER EJ,CARNEVALE J,PEDLEY C,et al. Referral frequency,attrition rate,and outcomes of germline testing in patients with pancreatic adenocarcinoma[J]. Fam Cancer,2018.[Epub ahead of print]
[37] KAWAKAMI H,ZAANAN A,SINICROPE FA. Microsatellite instability testing and its role in the management of colorectal cancer[J]. Curr Treat Options Oncol,2015,16(7):30.
[38] LEMERY S,KEEGAN P,PAZDUR R. First FDA Approval agnostic of cancer site-when a biomarker defines the indication[J]. N Engl J Med,2017,377(15):1409-1412.
[39] CHANG L,CHANG M,CHANG HM,et al. Microsatellite instability:A predictive biomarker for cancer immunotherapy[J].Appl Immunohistochem Mol Morphol,2018,26(2):e15-e21.
[40] EL-KHOUEIRY AB,SANGRO B,YAU T,et al. Nivolumab in patients with advanced hepatocellular carcinoma(CheckMate040):An open-label,non-comparative,phase 1/2 dose escalation and expansion trial[J]. Lancet, 2017, 389(10088):2492-2502.
[41] PATNAIK A,KANG SP,RASCO D,et al. Phase I study of pembrolizumab(MK-3475; anti-PD-1 monoclonal antibody)in patients with advanced solid tumors[J]. Clin Cancer Res,2015,21(19):4286-4293.
[42] WEISS GJ,BLAYDORN L,BECK J,et al. Phase Ib/II study of gemcitabine,nab-paclitaxel,and pembrolizumab in metastatic pancreatic adenocarcinoma[J]. Invest New Drugs,2018,36(1):96-102.
[43] COOK AM,LESTERHUIS WJ,NOWAK AK,et al. Chemotherapy and immunotherapy:Mapping the road ahead[J]. Curr Opin Immunol,2016,39:23-29.
[44] McDONNELL AM,LESTERHUIS WJ,KHONG A,et al. Tumor-infiltrating dendritic cells exhibit defective cross-presentation of tumor antigens,but is reversed by chemotherapy[J].Eur J Immunol,2015,45(1):49-59.
[45] HAYNES NM,van der MOST RG,LAKE RA,et al. Immunogenic anti-cancer chemotherapy as an emerging concept[J]. Curr Opin Immunol,2008,20(5):545-557.
[46] van der MOST RG,ROBINSON BW,LAKE RA. Combining immunotherapy with chemotherapy to treat cancer[J]. Discov Med,2005,5(27):265-270.
[47] VONDERHEIDE RH,GLENNIE MJ. Agonistic CD40 antibodies and cancer therapy[J]. Clin Cancer Res,2013,19(5):1035-1043.
[48] LONG KB,GLADNEY WL,TOOKER GM,et al. IFNgamma and CCL2 cooperate to redirect tumor-infiltrating monocytes to degrade fibrosis and enhance chemotherapy efficacy in pancreatic carcinoma[J]. Cancer Discov,2016,6(4):400-413.
[49] BEATTY GL,TORIGIAN DA,CHIOREAN EG,et al. A phase I study of an agonist CD40 monoclonal antibody(CP-870,893)in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma[J]. Clin Cancer Res,2013,19(22):6286-6295.
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