NF-κB RelA renders tumor-associated macrophages resistant to and capable of directly suppressing CD8+ T cells for tumor promotion

Liwen Li, Lei Han, Fan Sun, Jingjiao Zhou, Kim C. Ohaegbulam, Xudong Tang, Xingxing Zang, Kris A. Steinbrecher, Zhaoxia Qu, Gutian Xiao

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Activation of the inflammatory transcription factor NF-κB in tumor-associated macrophages (TAMs) is assumed to contribute to tumor promotion. However, whether and how NF-κB drives the antitumor macrophages to become pro-tumorigenic have not been determined in any cancer type yet. Similarly, how TAMs repress CD8+ cytotoxic T lymphocytes (CTLs) remains largely unknown, although their importance in regulatory T (Treg) cell regulation and tumor promotion has been well appreciated. Here, using an endogenous lung cancer model we uncover a direct crosstalk between TAMs and CTLs. TAMs suppress CTLs through the T-cell inhibitory molecule B7x (B7-H4/B7S1) in a cell-cell contact manner, whereas CTLs kill TAMs in a tumor antigen-specific manner. Remarkably, TAMs secrete the known T-cell suppressive cytokine interleukin-10 (IL-10) to activate, but not to repress, CTLs. Notably, one major role of cell-intrinsic NF-κB RelA is to drive TAMs to suppress CTLs for tumor promotion. It induces B7x expression in TAMs directly, and restricts IL-10 expression indirectly by repressing expression of the NF-κB cofactor Bcl3 and subsequent Bcl3/NF-κB1-mediated transcription of IL-10. It also renders TAMs resistant to CTLs by up-regulating anti-apoptotic genes. These studies help understand how immunity is shaped in lung tumorigenesis, and suggest a RelA-targeted immunotherapy for this deadliest cancer.

Original languageEnglish (US)
Article numbere1435250
JournalOncoImmunology
Volume7
Issue number6
DOIs
Publication statusPublished - Jun 3 2018

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Keywords

  • B7x/B7-H4/B7S1
  • IL-10
  • NF-κB
  • RelA/p65
  • immune checkpoint
  • lung cancer
  • tumor-associated macrophage

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

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