Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma impair CD8+ T cell activation and limit responsiveness to immunotherapy in mice

Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions, yet the potential for targeting such senescent cells for improved therapy remains largely unknown. Here, we uncover the presence of a senescent subset of cancer-associated fibroblasts (CAFs) within pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs represented different previously-defined CAF subtypes. Senescent CAFs isolated from mouse and humans expressed elevated levels of immunoregulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8+ T cells in mouse pancreatic carcinomas, whereas induction of CAF senescence had the opposite effect. Combining ABT-199 with an immune checkpoint therapy regimen significantly reduced mouse tumor burden. These results indicate that senescent CAFs in PDAC stroma limit the numbers of activated cytotoxic CD8+ T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.

肿瘤及其间质中的衰老细胞（senescent cells）可发挥复杂的促瘤与抑瘤双重功能，但靶向此类衰老细胞以优化治疗方案的潜力，在很大程度上仍未被阐明。本研究证实，在小鼠及人类的胰腺导管腺癌（pancreatic ductal adenocarcinomas, PDAC）与癌前病变中，存在一类衰老型癌相关成纤维细胞（cancer-associated fibroblasts, CAFs）亚群。此类衰老型CAFs并不隶属于单一亚型，而是涵盖了多种此前已被界定的CAF亚型。从小鼠及人类样本中分离得到的衰老型CAFs，其免疫调节基因（immunoregulatory genes）的表达水平显著上调。通过遗传学手段或使用Bcl-2抑制剂（Bcl-2 inhibitor）ABT-199（维奈克拉，venetoclax）清除衰老型CAFs，可提升小鼠胰腺癌组织中活化CD8+ T细胞的占比；而诱导CAFs发生衰老则会产生相反的效果。将ABT-199与免疫检查点治疗（immune checkpoint therapy）方案联合使用，可显著降低小鼠的肿瘤负荷（tumor burden）。上述结果表明，胰腺导管腺癌间质中的衰老型CAFs会抑制活化的细胞毒性CD8+ T细胞的数量，同时提示通过衰老细胞清除疗法（senolytic treatment）靶向清除此类细胞，或可增强免疫治疗的疗效。