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

Briana G. Nixon, Fengshen Kuo, Liang Liang 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, James J. Hsieh, Timothy A. Chan, Kenneth M. Murphy, James J. MoonA. Ari Hakimi, Ming O. Li

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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.

Original languageEnglish
Pages (from-to)2044-2058.e5
JournalImmunity
Volume55
Issue number11
DOIs
StatePublished - Nov 8 2022

Keywords

  • IRF8
  • T cell exhaustion
  • antigen presentation
  • antigen-presenting cell
  • tumor-associated macrophage

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