Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Discov. 2022 Jun 2;12(6):1580-1597. doi: 10.1158/2159-8290.CD-20-1484.
The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of fibroblasts as part of the host response to cancer. Using single-cell RNA sequencing, multiplex immunostaining, and several genetic mouse models, we identify carcinoma-associated fibroblasts (CAF) with opposing functions in PDAC progression. Depletion of fibroblast activation protein (FAP)+ CAFs results in increased survival, in contrast to depletion of alpha smooth muscle actin (αSMA)+ CAFs, which leads to decreased survival. Tumor-promoting FAP+ CAFs (TP-CAF) and tumor-restraining αSMA+ CAFs (TR-CAF) differentially regulate cancer-associated pathways and accumulation of regulatory T cells. Improved efficacy of gemcitabine is observed when IL6 is deleted from αSMA+ CAFs but not from FAP+ CAFs using dual-recombinase genetic PDAC models. Improved gemcitabine efficacy due to lack of IL6 synergizes with anti-PD-1 immunotherapy to significantly improve survival of PDAC mice. Our study identifies functional heterogeneity of CAFs in PDAC progression and their different roles in therapy response.
PDAC is associated with accumulation of dense stroma consisting of fibroblasts and extracellular matrix that regulate tumor progression. Here, we identify two distinct populations of fibroblasts with opposing roles in the progression and immune landscape of PDAC. Our findings demonstrate that fibroblasts are functionally diverse with therapeutic implications. This article is highlighted in the In This Issue feature, p. 1397.
胰腺导管腺癌 (PDAC) 的肿瘤微环境涉及大量成纤维细胞的积累，这是宿主对癌症反应的一部分。通过单细胞 RNA 测序、多重免疫染色和几种遗传小鼠模型，我们确定了在 PDAC 进展中具有相反功能的癌相关成纤维细胞 (CAF)。与耗尽α平滑肌肌动蛋白 (αSMA)+CAFs 导致存活减少相反，耗尽成纤维细胞激活蛋白 (FAP)+CAFs 导致存活增加。促进肿瘤的 FAP+CAFs (TP-CAF) 和抑制肿瘤的 αSMA+CAFs (TR-CAF) 差异调节癌症相关途径和调节性 T 细胞的积累。使用双重重组酶遗传 PDAC 模型，当从 αSMA+CAFs 中删除 IL6 而不是从 FAP+CAFs 中删除时，观察到吉西他滨的疗效提高。由于缺乏 IL6，吉西他滨的疗效提高与抗 PD-1 免疫疗法协同作用，可显著提高 PDAC 小鼠的生存率。我们的研究确定了 PDAC 进展中 CAF 的功能异质性及其在治疗反应中的不同作用。
PDAC 与由成纤维细胞和细胞外基质组成的致密基质的积累有关，这些基质调节肿瘤的进展。在这里，我们确定了两种具有相反作用的不同成纤维细胞群体，它们在 PDAC 的进展和免疫景观中具有不同的作用。我们的研究结果表明，成纤维细胞具有功能多样性，具有治疗意义。本文在本期特色文章中重点介绍，第 1397 页。
