Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, United States.
Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, United States.
Front Immunol. 2021 Jan 28;11:613815. doi: 10.3389/fimmu.2020.613815. eCollection 2020.
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with an overall 5-year survival rate of 10%. Disease lethality is due to late diagnosis, early metastasis and resistance to therapy, including immunotherapy. PDA creates a robust fibroinflammatory tumor microenvironment that contributes to immunotherapy resistance. While previously considered an immune privileged site, evidence demonstrates that in some cases tumor antigen-specific T cells infiltrate and preferentially accumulate in PDA and are central to tumor cell clearance and long-term remission. Nonetheless, PDA can rapidly evade an adaptive immune response using a myriad of mechanisms. Mounting evidence indicates PDA interferes with T cell differentiation into potent cytolytic effector T cells deficiencies in naive T cell priming, inducing T cell suppression or promoting T cell exhaustion. Mechanistic research indicates that immunotherapy combinations that change the suppressive tumor microenvironment while engaging antigen-specific T cells is required for treatment of advanced disease. This review focuses on recent advances in understanding mechanisms limiting T cell function and current strategies to overcome immunotherapy resistance in PDA.
胰腺导管腺癌 (PDA) 是一种致命的恶性肿瘤，整体 5 年生存率为 10%。疾病的致命性是由于诊断较晚、早期转移和对治疗的耐药性，包括免疫治疗。PDA 会产生强大的纤维炎症肿瘤微环境，导致免疫治疗耐药。尽管之前被认为是免疫特权部位，但有证据表明，在某些情况下，肿瘤抗原特异性 T 细胞浸润并优先积聚在 PDA 中，这是清除肿瘤细胞和长期缓解的关键。尽管如此，PDA 可以通过多种机制迅速逃避适应性免疫反应。越来越多的证据表明，PDA 干扰 T 细胞分化为有效的细胞毒性效应 T 细胞，在初始 T 细胞启动时存在缺陷，诱导 T 细胞抑制或促进 T 细胞耗竭。机制研究表明，需要改变抑制性肿瘤微环境的免疫治疗组合，同时结合抗原特异性 T 细胞，才能治疗晚期疾病。本综述重点介绍了目前对限制 T 细胞功能的机制的理解进展，以及克服 PDA 免疫治疗耐药性的当前策略。
