Tumor-associated macrophages expressing the transcription factor IRF8 promote T cell exhaustion in cancer. Academic Article uri icon

Overview

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.

publication date

  • October 25, 2022

Research

keywords

  • Carcinoma, Renal Cell
  • Kidney Neoplasms

Identity

PubMed Central ID

  • PMC9649891

Scopus Document Identifier

  • 85141307944

Digital Object Identifier (DOI)

  • 10.1016/j.immuni.2022.10.002

PubMed ID

  • 36288724

Additional Document Info

volume

  • 55

issue

  • 11