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

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)
JournalOncoImmunology
DOIs
StateAccepted/In press - Feb 26 2018

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Macrophages
T-Lymphocytes
Cytotoxic T-Lymphocytes
Neoplasms
Interleukin-10
Regulatory T-Lymphocytes
B7 Antigens
Neoplasm Antigens
Immunotherapy
Immunity
Lung Neoplasms
Carcinogenesis
Transcription Factors
Cytokines
Lung

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

Cite this

NF-κB RelA renders tumor-associated macrophages resistant to and capable of directly suppressing CD8+ T cells for tumor promotion. / Li, Liwen; Han, Lei; Sun, Fan; Zhou, Jingjiao; Ohaegbulam, Kim C.; Tang, Xudong; Zang, Xingxing; Steinbrecher, Kris A.; Qu, Zhaoxia; Xiao, Gutian.

In: OncoImmunology, 26.02.2018.

Research output: Contribution to journalArticle

Li, Liwen ; Han, Lei ; Sun, Fan ; Zhou, Jingjiao ; Ohaegbulam, Kim C. ; Tang, Xudong ; Zang, Xingxing ; Steinbrecher, Kris A. ; Qu, Zhaoxia ; Xiao, Gutian. / NF-κB RelA renders tumor-associated macrophages resistant to and capable of directly suppressing CD8+ T cells for tumor promotion. In: OncoImmunology. 2018.
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AU - Li, Liwen

AU - Han, Lei

AU - Sun, Fan

AU - Zhou, Jingjiao

AU - Ohaegbulam, Kim C.

AU - Tang, Xudong

AU - Zang, Xingxing

AU - Steinbrecher, Kris A.

AU - Qu, Zhaoxia

AU - Xiao, Gutian

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AB - 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.

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KW - RelA/p65

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