Immune-checkpoint blockade (ICB) promotes antitumor immune responses and can result in durable patient benefit. However, response rates in breast cancer patients remain modest, stimulating efforts to discover novel treatment options. Cancer-associated fibroblasts (CAF) represent a major component of the breast tumor microenvironment and have known immunosuppressive functions in addition to their well-established roles in directly promoting tumor growth and metastasis. Here we utilized paired syngeneic mouse mammary carcinoma models to show that CAF abundance is associated with insensitivity to combination αCTLA4 and αPD-L1 ICB. CAF-rich tumors exhibited an immunologically cold tumor microenvironment, with transcriptomic, flow cytometric, and quantitative histopathologic analyses demonstrating a relationship between CAF density and a CD8+ T-cell–excluded tumor phenotype. The CAF receptor Endo180 (Mrc2) is predominantly expressed on myofibroblastic CAFs, and its genetic deletion depleted a subset of αSMA-expressing CAFs and impaired tumor progression in vivo. The addition of wild-type, but not Endo180-deficient, CAFs in coimplantation studies restricted CD8+ T-cell intratumoral infiltration, and tumors in Endo180 knockout mice exhibited increased CD8+ T-cell infiltration and enhanced sensitivity to ICB compared with tumors in wild-type mice. Clinically, in a trial of melanoma patients, high MRC2 mRNA levels in tumors were associated with a poor response to αPD-1 therapy, highlighting the potential benefits of therapeutically targeting a specific CAF subpopulation in breast and other CAF-rich cancers to improve clinical responses to immunotherapy. Significance: Paired syngeneic models help unravel the interplay between CAF and tumor immune evasion, highlighting the benefits of targeting fibroblast subpopulations to improve clinical responses to immunotherapy.

中文翻译：

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癌症相关成纤维细胞抑制 CD8+ T 细胞浸润并赋予对免疫检查点阻断的抵抗力

免疫检查点阻断（ICB）可促进抗肿瘤免疫反应，并可为患者带来持久的益处。然而，乳腺癌患者的缓解率仍然较低，这刺激了人们探索新治疗方案的努力。癌症相关成纤维细胞（CAF）是乳腺肿瘤微环境的主要组成部分，除了直接促进肿瘤生长和转移的明确作用外，还具有已知的免疫抑制功能。在这里，我们利用配对同基因小鼠乳腺癌模型来证明 CAF 丰度与对 αCTLA4 和 αPD-L1 ICB 组合的不敏感性相关。富含 CAF 的肿瘤表现出免疫冷肿瘤微环境，通过转录组学、流式细胞术、定量组织病理学分析证明了 CAF 密度与 CD8+ T 细胞排除的肿瘤表型之间的关系。CAF 受体 Endo180 (Mrc2) 主要在肌成纤维细胞 CAF 上表达，其基因缺失耗尽了表达 αSMA 的 CAF 子集，并损害了体内肿瘤进展。在共植入研究中添加野生型而非Endo180缺陷型CAF限制了CD8+ T细胞瘤内浸润，与野生型肿瘤相比，Endo180敲除小鼠的肿瘤表现出CD8+ T细胞浸润增加和对ICB的敏感性增强老鼠。临床上，在黑色素瘤患者的一项试验中，肿瘤中高 MRC2 mRNA 水平与 αPD-1 治疗反应不佳相关，强调了针对乳腺癌和其他富含 CAF 的癌症中的特定 CAF 亚群进行治疗的潜在益处，以改善对免疫疗法的临床反应。意义：配对同基因模型有助于揭示 CAF 和肿瘤免疫逃避之间的相互作用，突出了靶向成纤维细胞亚群以改善免疫治疗临床反应的好处。