Tumor Microenvironment-Derived R-spondins Enhance Antitumor Immunity to Suppress Tumor Growth and Sensitize for Immune Checkpoint Blockade Therapy.

Abstract

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 immunity in the TME and implications for a putative R-spondin-LGR6 axis in regulating NK-cell biology. This article is highlighted in the In This Issue feature, p. 2945.

• Authors: Yuting Tang, Qian Xu, Liang Hu, Xiaomei Yan, Xiaomin Feng, Asumi Yokota, Weinan Wang, Di Zhan, Durga Krishnamurthy, David E Ochayon, Lijun Wen, Li Huo, Huimin Zeng, Yingwan Luo, L Frank Huang, Mark Wunderlich, Jiwang Zhang, Eric Vivier, Jianfeng Zhou, Stephen N Waggoner, Gang Huang
• Journal: Cancer discovery (Cancer Discov) Vol. 11 Issue 12 Pg. 3142-3157 (12 01 2021) ISSN: 2159-8290 [Electronic] United States
• PMID: 34193438 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Immune Checkpoint Inhibitors

Topics

• Endothelial Cells
• Humans
• Immune Checkpoint Inhibitors
• Immunotherapy
• Neoplasms (drug therapy, genetics)
• Tumor Microenvironment