Journal
ONCOIMMUNOLOGY
Volume 7, Issue 6, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2018.1435250
Keywords
B7x; B7-H4; B7S1; immune checkpoint; IL-10; lung cancer; NF-kappa B; RelA/p65; tumor-associated macrophage
Categories
Funding
- HHS \ National Institutes of Health (NIH)
Ask authors/readers for more resources
Activation of the inflammatory transcription factor NF-kappa B in tumor-associated macrophages (TAMs) is assumed to contribute to tumor promotion. However, whether and how NF-kappa B 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-kappa B 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-kappa B cofactor Bcl3 and subsequent Bcl3/NF-kappa B1-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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available