Service d'Oncologie Médicale, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris Est Créteil, Créteil 94010, France.
Université de Lyon, Université Claude Bernard Lyon 1, Inserm U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon 69008, France.
World J Gastroenterol. 2018 May 28;24(20):2137-2151. doi: 10.3748/wjg.v24.i20.2137.
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, mostly due to its resistance to treatment. Of these, checkpoint inhibitors (CPI) are inefficient when used as monotherapy, except in the case of a rare subset of tumors harboring microsatellite instability (< 2%). This inefficacy mainly resides in the low immunogenicity and non-inflamed phenotype of PDAC. The abundant stroma generates a hypoxic microenvironment and drives the recruitment of immunosuppressive cells through cancer-associated-fibroblast activation and transforming growth factor β secretion. Several strategies have recently been developed to overcome this immunosuppressive microenvironment. Combination therapies involving CPI aim at increasing tumor immunogenicity and promoting the recruitment and activation of effector T cells. Ongoing studies are therefore exploring the association of CPI with vaccines, oncolytic viruses, MEK inhibitors, cytokine inhibitors, and hypoxia- and stroma-targeting agents. Adoptive T-cell transfer is also under investigation. Moreover, translational studies on tumor tissue and blood, prior to and during treatment may lead to the identification of biomarkers with predictive value for both clinical outcome and response to immunotherapy.
胰腺导管腺癌（PDAC）是最致命的癌症之一，主要是因为其对治疗的耐药性。其中，除了少数携带有微卫星不稳定性（< 2%）的肿瘤外，检查点抑制剂（CPI）作为单一疗法效率不高。这种无效性主要源于 PDAC 的低免疫原性和非炎症表型。丰富的基质会产生缺氧微环境，并通过癌症相关成纤维细胞的激活和转化生长因子β的分泌来招募免疫抑制细胞。最近已经开发了几种策略来克服这种免疫抑制微环境。包括 CPI 在内的联合疗法旨在提高肿瘤的免疫原性，并促进效应 T 细胞的募集和激活。目前正在探索 CPI 与疫苗、溶瘤病毒、MEK 抑制剂、细胞因子抑制剂以及缺氧和基质靶向药物的联合应用。过继性 T 细胞转移也在研究中。此外，在治疗前和治疗期间对肿瘤组织和血液进行转化研究，可能会发现对临床结果和免疫治疗反应都有预测价值的生物标志物。
