Pancreatic ductal adenocarcinoma (PDAC) therapeutic resistance is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer-associated fibroblasts (CAF). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAF) in mouse and human PDAC. These SenCAFs are a phenotypically distinct subset of myofibroblastic CAFs that localize near tumor ducts and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we used an LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Depletion of senescent stromal cells in genetic and pharmacologic PDAC models relieved immune suppression by macrophages, delayed tumor progression, and increased responsiveness to chemotherapy. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immune cell dysfunction. Significance: CAF heterogeneity in PDAC remains poorly understood. In this study, we identify a novel subpopulation of senescent CAFs that promotes PDAC progression and immunosuppression. Targeting CAF senescence in combination therapies could increase tumor vulnerability to chemo- or immunotherapy. See related article by Ye et al.

中文翻译：

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衰老定义了肌成纤维细胞的一个独特亚群，其协调胰腺癌的免疫抑制

胰腺导管腺癌（PDAC）治疗耐药很大程度上归因于独特的肿瘤微环境，其中含有丰富的癌症相关成纤维细胞（CAF）。最近确定了不同的 CAF 群体，但 CAF 异质性的表型驱动因素和具体影响仍不清楚。在这项研究中，我们鉴定了小鼠和人类 PDAC 中衰老肌纤维母细胞 CAF (SenCAF) 的亚群。这些 SenCAF 是肌成纤维细胞 CAF 的一个表型独特的子集，位于肿瘤导管附近并随着 PDAC 进展而积累。为了评估内源性 SenCAF 对 PDAC 的影响，我们使用了可诱导衰老细胞耗竭的自发 PDAC 小鼠模型 LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA)。在遗传和药理学 PDAC 模型中，衰老基质细胞的消耗可以缓解巨噬细胞的免疫抑制，延缓肿瘤进展，并增加对化疗的反应。总的来说，我们的研究结果表明 SenCAF 促进 PDAC 进展和免疫细胞功能障碍。意义：PDAC 中的 CAF 异质性仍然知之甚少。在这项研究中，我们发现了一种新的衰老 CAF 亚群，可促进 PDAC 进展和免疫抑制。联合治疗中针对 CAF 衰老可能会增加肿瘤对化疗或免疫治疗的脆弱性。参见叶等人的相关文章。