Tumor-associated macrophages expressing the transcription factor IRF8 promote T cell exhaustion in cancer. Immunity. 2022 Nov 08; 55(11):2044-2058.e5.

Citation

Nixon BG, Kuo F, Ji L, Liu M, Capistrano K, Do M, Franklin RA, Wu X, Kansler ER, Srivastava RM, Purohit TA, Sanchez A, Vuong L, Krishna C, Wang X, Morse Iii HC, Hsieh JJ, Chan TA, Murphy KM, Moon JJ, Hakimi AA, Li MO. 2022. Tumor-associated macrophages expressing the transcription factor IRF8 promote T cell exhaustion in cancer. Immunity. 55(11):2044-2058.e5. Pubmed: 36288724 DOI:S1074-7613(22)00543-X

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.

Related Faculty

Ruth Franklin, Ph.D.

Franklin Lab

Ruth Franklin’s laboratory explores the role of the innate immune system in tissue repair and homeostasis, with a focus on the communication between macrophages and non-immune cells within tissues.