美国纪念斯隆-凯特琳癌症中心Ming O. Li团队近期取得重要工作进展，他们研究发现表达转录因子IRF8的肿瘤相关巨噬细胞在癌症中促进T细胞耗竭。相关论文2022年10月25日在线发表于《免疫》杂志上。

研究人员在乳腺癌小鼠模型中检测了癌症如何影响单核吞噬抗原提呈细胞（APCs）。肿瘤诱导单核细胞来源的肿瘤相关巨噬细胞（TAMs）的扩增和1型树突状细胞（DC1s）的激活，这两种细胞都表达并需要转录因子干扰素调节因子8（IRF8）。尽管DC1s在肿瘤引流淋巴结中介导了细胞毒性T淋巴细胞（CTL）的启动，但TAMs促进了肿瘤中CTL的耗竭，而且IRF8是TAMs呈现癌细胞抗原能力所必需的。TAM特异性的IRF8缺失可以防止癌细胞反应性CTL的耗尽，并抑制肿瘤的生长。来自免疫浸润的肾细胞癌患者的肿瘤有大量的TAMs表达IRF8，并富含IRF8基因表达特征。

此外，TAM-IRF8特征与多种癌症类型的CTL耗竭特征共存。因此，CTL耗竭是由TAMs通过IRF8促进的。

据介绍，肿瘤由抗原提呈细胞组成，包括具有不同起源和功能的巨噬细胞亚群。

附：英文原文 

Title: Tumor-associated macrophages expressing the transcription factor IRF8 promote T cell exhaustion in cancer

Author: Briana G. Nixon, Fengshen Kuo, LiangLiang Ji, Ming Liu, Kristelle Capistrano, Mytrang Do, Ruth A. Franklin, Xiaodi Wu, Emily R. Kansler, Raghvendra M. Srivastava, Tanaya A. Purohit, Alejandro Sanchez, Lynda Vuong, Chirag Krishna, Xinxin Wang, Herbert C. Morse III, James J. Hsieh, Timothy A. Chan, Kenneth M. Murphy, James J. Moon, A. Ari Hakimi, Ming O. Li

Issue&Volume: 2022-10-25

Abstract: 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.

DOI: 10.1016/j.immuni.2022.10.002

Source: https://www.cell.com/immunity/fulltext/S1074-7613(22)00543-X