FAP Delineates Heterogeneous and Functionally Divergent Stromal Cells in Immune-Excluded Breast Tumors.
FAP Delineates Heterogeneous and Functionally Divergent Stromal Cells in Immune-Excluded Breast Tumors.
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DOI：
10.1158/2326-6066.cir-18-0098
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发表时间：
2018-12
影响因子：
10.1
通讯作者：
Turley SJ
中科院分区：
文献类型：
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作者：
Cremasco V;Astarita JL;Grauel AL;Keerthivasan S;MacIsaac K;Woodruff MC;Wu M;Spel L;Santoro S;Amoozgar Z;Laszewski T;Migoni SC;Knoblich K;Fletcher AL;LaFleur M;Wucherpfennig KW;Pure E;Dranoff G;Carroll MC;Turley SJ
肿瘤相关成纤维细胞(CAF)通常与不良的临床结局有关。CAF以多种方式支持肿瘤生长，并可抑制抗肿瘤免疫和对免疫治疗的反应。然而，对CAF在肿瘤生长和治疗反应中的作用缺乏准确的了解。这一研究领域的差异可能源于肿瘤微环境中成纤维细胞的组成和功能的异质性。此外，CAF是否直接与T细胞相互作用并抑制T细胞尚不清楚。在这里，小鼠和人类乳腺肿瘤被用来检测表达成纤维细胞激活蛋白(FAP)的基质细胞，成纤维细胞激活蛋白(FAP)是CAF的表面标志。根据pDPN的表达鉴定出两个离散的FAP+间充质细胞群体：FAP+PDPN+CAF群体和FAP+PDPN⁻群体的癌症相关周细胞(CAP)。虽然两个亚群都表达细胞外基质分子，但与CAPS相比，CAF转录组富含与转化生长因子β信号和纤维化相关的基因。此外，CAF在肿瘤外缘与T细胞密切接触，而CAF则分布在血管周围。FAP+PDPN+CAF以一氧化氮依赖的方式抑制T细胞的增殖，而FAP+PDPN+CAF对⁻周细胞无免疫抑制作用。总而言之，这些发现表明，乳腺肿瘤包含多种表达FAP的基质细胞，它们的功能、表型和位置都是二分的。
Cancer-associated fibroblasts (CAFs) are generally associated with poor clinical outcome. CAFs support tumor growth in a variety of ways and can suppress antitumor immunity and response to immunotherapy. However, a precise understanding of CAF contributions to tumor growth and therapeutic response is lacking. Discrepancies in this field of study may stem from heterogeneity in composition and function of fibroblasts in the tumor microenvironment. Furthermore, it remains unclear whether CAFs directly interact with and suppress T cells. Here, mouse and human breast tumors were used to examine stromal cells expressing fibroblast activation protein (FAP), a surface marker for CAFs. Two discrete populations of FAP+ mesenchymal cells were identified on the basis of podoplanin (PDPN) expression: a FAP+PDPN+ population of CAFs and a FAP+PDPN⁻ population of cancer-associated pericytes (CAPs). Although both subsets expressed extracellular matrix molecules, the CAF transcriptome was enriched in genes associated with TGFβ signaling and fibrosis compared with CAPs. In addition, CAFs were enriched at the outer edge of the tumor, in close contact with T cells, whereas CAPs were localized around vessels. Finally, FAP+PDPN+ CAFs suppressed the proliferation of T cells in a nitric oxide-dependent manner whereas FAP+PDPN⁻ pericytes were not immunosuppressive. Collectively, these findings demonstrate that breast tumors contain multiple populations of FAP-expressing stromal cells of dichotomous function, phenotype, and location.