Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA.
Immunogenomics & Precision Oncology Platform (IPOP), Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Immunity. 2022 Nov 8;55(11):2044-2058.e5. doi: 10.1016/j.immuni.2022.10.002. Epub 2022 Oct 25.
Tumors are populated by antigen-presenting cells (APCs) including macrophage subsets with distinct origins and functions. Here, we examined how cancer impacts mononuclear phagocytic APCs in a murine model of breast cancer. Tumors induced the expansion of monocyte-derived tumor-associated macrophages (TAMs) and the activation of type 1 dendritic cells (DC1s), both of which expressed and required the transcription factor interferon regulatory factor-8 (IRF8). Although DC1s mediated cytotoxic T lymphocyte (CTL) priming in tumor-draining lymph nodes, TAMs promoted CTL exhaustion in the tumor, and IRF8 was required for TAMs' ability to present cancer cell antigens. TAM-specific IRF8 deletion prevented exhaustion of cancer-cell-reactive CTLs and suppressed tumor growth. Tumors from patients with immune-infiltrated renal cell carcinoma had abundant TAMs that expressed IRF8 and were enriched for an IRF8 gene expression signature. Furthermore, the TAM-IRF8 signature co-segregated with CTL exhaustion signatures across multiple cancer types. Thus, CTL exhaustion is promoted by TAMs via IRF8.
肿瘤中存在抗原呈递细胞（APCs），包括具有不同起源和功能的巨噬细胞亚群。在这里，我们研究了癌症如何影响乳腺癌小鼠模型中单核吞噬 APC。肿瘤诱导单核细胞衍生的肿瘤相关巨噬细胞（TAMs）的扩张和 1 型树突状细胞（DC1s）的激活，两者均表达并需要转录因子干扰素调节因子-8（IRF8）。虽然 DC1s 在肿瘤引流淋巴结中介导细胞毒性 T 淋巴细胞（CTL）的启动，但 TAMs 在肿瘤中促进 CTL 衰竭，并且 IRF8 是 TAMs 呈现癌细胞抗原的能力所必需的。TAM 特异性 IRF8 缺失可防止与癌细胞反应的 CTL 衰竭，并抑制肿瘤生长。具有免疫浸润性肾细胞癌的患者的肿瘤中存在丰富的表达 IRF8 的 TAMs，并且富含 IRF8 基因表达特征。此外，TAM-IRF8 特征与多种癌症类型的 CTL 衰竭特征共分离。因此，CTL 衰竭是由 TAMs 通过 IRF8 促进的。
