Gössling Gustavo C L, Zhen David B, Pillarisetty Venu G, Chiorean E Gabriela
Department of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
Expert Rev Clin Immunol. 2022 Nov;18(11):1173-1186. doi: 10.1080/1744666X.2022.2120471. Epub 2022 Sep 11.
Immune checkpoint inhibitors (ICI) have not yielded significant efficacy in pancreatic ductal adenocarcinoma (PDA), despite the role of the innate and adaptive immune systems on progression and survival. However, recently identified pathways have identified new targets and generated promising clinical investigations into promoting an effective immune-mediated antitumor response in PDA.
We review biological mechanisms associated with immunotherapy resistance and outline strategies for therapeutic combinations with established and novel therapies in PDA.
Pancreatic cancers rarely benefit from treatment with ICI due to an immunosuppressive tumor microenvironment (TME). New understandings of factors associated with the suppressive TME include low- and poor-quality neoantigens, constrained effector T cells infiltration, and the presence of a dense, suppressive myeloid cell population. These findings have been translated into new clinical investigations evaluating novel therapies in combination with ICI and/or standard systemic chemotherapy and radiotherapy. The epithelial, immune, and stromal compartments are intricately related in PDA, and the framework for successful targeting of this disease requires a comprehensive and personalized approach.
尽管先天性和适应性免疫系统在胰腺导管腺癌（PDA）的进展和生存中发挥作用，但免疫检查点抑制剂（ICI）在PDA中尚未产生显著疗效。然而，最近发现的途径已确定了新的靶点，并开展了有前景的临床研究，以促进PDA中有效的免疫介导抗肿瘤反应。
我们回顾了与免疫治疗耐药相关的生物学机制，并概述了PDA中与既定疗法和新疗法联合治疗的策略。
由于免疫抑制性肿瘤微环境（TME），胰腺癌很少从ICI治疗中获益。对与抑制性TME相关因素的新认识包括低质量和劣质新抗原、效应T细胞浸润受限以及存在密集的抑制性髓样细胞群体。这些发现已转化为新的临床研究，评估新疗法与ICI和/或标准全身化疗及放疗联合使用的效果。在PDA中，上皮、免疫和基质成分密切相关，成功靶向该疾病的框架需要全面且个性化的方法。
