期刊
CANCER DISCOVERY
卷 11, 期 12, 页码 3142-3157出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-20-0833
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资金
- NIH [R01DK105014, 1R01CA248019, DA038017, AI148080, AR073228]
- CCTST Pilot Collaborative Studies Grant
- Taub Foundation
- EvansMDS Foundation
- National Natural Science Foundation of China [81570196]
- American Heart Association
- Arnold W. Strauss Fellow Award
- Pelotonia postdoctoral fellowship
R-spondin 3 expression is associated with favorable prognosis and enhances infiltration and function of NK cells and T cells in tumors, leading to tumor regression, and also increases tumor sensitivity to anti-PD-1 therapy.
Natural killer (NK) cells and T cells are key effectors of antitumor immune responses and major targets of checkpoint inhibitors. In multiple cancer types, we find that the expression of Wnt signaling potentiator R-spondin genes (e.g., RSPO3) is associated with favorable prognosis and positively correlates with gene signatures of both NK cells and T cells. Although endothelial cells and cancer-associated fibroblasts comprise the R-spondin 3-producing cells, NK cells and T cells correspondingly express the R-spondin 3 receptor LGR6 within the tumor microenvironment (TME). Exogenous expression or intratumor injection of R-spondin 3 in tumors enhanced the infiltration and function of cytotoxic effector cells, which led to tumor regression. NK cells and CD8+T cells independently and cooperatively contributed to R-spondin 3-induced control of distinct tumor types. The effect of R-spondin 3 was mediated in part through upregulation of MYC and ribosomal biogenesis. Importantly, R-spondin 3 expression enhanced tumor sensitivity to anti-PD-1 therapy, thereby highlighting new therapeutic avenues.SIGNIFICANCE: Our study identifies novel targets in enhancing antitumor immunity and sensitizing immune checkpoint inhibition, which provides a rationale for developing new immunotherapies against cancers. It also offers mechanistic insights on Wnt signaling-mediated modulation of anticancer immu-nity in the TME and implications for a putative R-spondin-LGR6 axis in regulating NK-cell biology.
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