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

• Published in: Immunity (Cambridge, Mass.) Vol. 55; no. 11; pp. 2044 - 2058.e5
• Main Authors: Nixon, Briana G., Kuo, Fengshen, Ji, LiangLiang, Liu, Ming, Capistrano, Kristelle, Do, Mytrang, Franklin, Ruth A., Wu, Xiaodi, Kansler, Emily R., Srivastava, Raghvendra M., Purohit, Tanaya A., Sanchez, Alejandro, Vuong, Lynda, Krishna, Chirag, Wang, Xinxin, Morse III, Herbert C., Hsieh, James J., Chan, Timothy A., Murphy, Kenneth M., Moon, James J., Hakimi, A. Ari, Li, Ming O.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.11.2022
• Subjects: Animals; antigen presentation; antigen-presenting cell; Carcinoma, Renal Cell; Dendritic Cells; Humans; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; IRF8; Kidney Neoplasms; Mice; T cell exhaustion; T-Lymphocytes, Cytotoxic; tumor-associated macrophage; Tumor-Associated Macrophages; T cell exhaustion; tumor-associated macrophage; IRF8; antigen presentation; antigen-presenting cell
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2022.10.002

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. [Display omitted] •IRF8-expressing TAMs present cancer cell antigens and drive CTL exhaustion•MafBiCreIrf8flPyMT mice lose TAM antigen presentation, gain anti-tumor CTL response•TAMs from human cancer patients express IRF8 and an IRF8-dependent gene program•A TAM-IRF8 gene signature tracks with CTL exhaustion in multiple human malignancies Macrophages of distinct origin and function populate tumors. Nixon et al. examine how cancer impacts mononuclear phagocytic antigen-presenting cells and find that monocyte-derived tumor-associated macrophages (TAMs) present cancer cell antigens and drive cytotoxic T cell exhaustion, promoting tumor growth in a manner dependent on the transcription factor IRF8.