TY - JOUR
T1 - Tumor Microenvironment–Derived R-spondins Enhance Antitumor Immunity to Suppress Tumor Growth and Sensitize for Immune Checkpoint Blockade Therapy
AU - Tang, Yuting
AU - Xu, Qian
AU - Hu, Liang
AU - Yan, Xiaomei
AU - Feng, Xiaomin
AU - Yokota, Asumi
AU - Wang, Weinan
AU - Zhan, Di
AU - Krishnamurthy, Durga
AU - Ochayon, David E.
AU - Wen, Lijun
AU - Huo, Li
AU - Zeng, Huimin
AU - Luo, Yingwan
AU - Huang, L. Frank
AU - Wunderlich, Mark
AU - Zhang, Jiwang
AU - Vivier, Eric
AU - Zhou, Jianfeng
AU - Waggoner, Stephen N.
AU - Huang, Gang
N1 - Funding Information:
The authors thank G. Freudiger, M. Rife, A. Woeste, P. Seig, L. Tilton, and C. Sexton (Cincinnati Children’s Hospital Medical Center) for experiment assistance; X. Pan for bioinformatics analysis inquiry; Dr. H.L. Grimes (Cincinnati Children’s Hospital Medical Center) for kindly providing the MycG/G mice; and Dr. J.S. Palumbo (Cincinnati Children’s Hospital Medical Center) for kindly providing the YAC-1 cell line. They thank Cincinnati Children’s Research Flow Cytometry Core in the Division of Rheumatology, Cincinnati Children’s Veterinary Services, and J. Bailey and V. Summey (Cincinnati Children’s Comprehensive Mouse and Cancer Core) for experiment assistance. RNA-seq was conducted by the Genomics, Epigenomics and Sequencing Core, Department of Environmental Health, University of Cincinnati. A part of RNA-seq analyses was conducted by X. Zhang, J. Chen, and M. Med-vedovic at the Laboratory for Statistical Genomics and Systems Biology, Department of Environmental Health, University of Cincinnati. The results shown in this work are in part based upon data generated by the TCGA Research Network(https://www.cancer.gov/tcg). This work was supported by the NIH (R01DK105014 and 1R01CA248019, to G. Huang; DA038017, AI148080, and AR073228, to S.N. Waggoner), the CCTST Pilot Collaborative Studies Grant (to G. Huang), the Taub Foundation and EvansMDS Foundation (to G. Huang), National Natural Science Foundation of China (81570196, to J. Zhou), the Arnold W. Strauss Fellow Award (to Y. Tang), a Pelotonia postdoctoral fellowship (to Y. Tang; any opinions, findings, and conclusions expressed in this material are those of the authors and do not necessarily reflect those of the Pelotonia Fellowship Program or The Ohio State University), and a postdoctoral fellowship from the American Heart Association (to D.E. Ochayon).
Funding Information:
Y. Tang reports other support from Pelotonia Fellowship Program and an Arnold W. Strauss Fellow Award during the conduct of the study, as well as a patent for 63/034,010 pending. E. Vivier reports other support from Innate Pharma outside the submitted work. S.N. Waggoner reports grants from NIH and American Heart Association during the conduct of the study, as well as grants from NIH and Clinical Biosafety Services, and nonfinancial support from Synchronicity and Atomwise Inc. outside the submitted work. G. Huang reports grants from NIH, CCTST Pilot Collaborative Studies, and Taub Foundation and EvansMDS Foundation during the conduct of the study, as well as a patent for 63/034,010 pending. No disclosures were reported by the other authors.
Funding Information:
The authors thank G. Freudiger, M. Rife, A. Woeste, P. Seig, L. Tilton, and C. Sexton (Cincinnati Children?s Hospital Medical Center) for experiment assistance; X. Pan for bioinformatics analysis inquiry; Dr. H.L. Grimes (Cincinnati Children?s Hospital Medical Center) for kindly providing the MycG/G mice; and Dr. J.S. Palumbo (Cincinnati Children?s Hospital Medical Center) for kindly providing the YAC-1 cell line. They thank Cincinnati Children?s Research Flow Cytometry Core in the Division of Rheumatology, Cincinnati Children?s Veterinary Services, and J. Bailey and V. Summey (Cincinnati Children?s Comprehensive Mouse and Cancer Core) for experiment assistance. RNA-seq was conducted by the Genomics, Epigenomics and Sequencing Core, Department of Environmental Health, University of Cincinnati. A part of RNA-seq analyses was conducted by X. Zhang, J. Chen, and M. Med-vedovic at the Laboratory for Statistical Genomics and Systems Biology, Department of Environmental Health, University of Cincinnati. The results shown in this work are in part based upon data generated by the TCGA Research Network(https://www.cancer.gov/tcg). This work was supported by the NIH (R01DK105014 and 1R01CA248019, to G. Huang; DA038017, AI148080, and AR073228, to S.N. Waggoner), the CCTST Pilot Collaborative Studies Grant (to G. Huang), the Taub Foundation and EvansMDS Foundation (to G. Huang), National Natural Science Foundation of China (81570196, to J. Zhou), the Arnold W. Strauss Fellow Award (to Y. Tang), a Pelotonia postdoctoral fellowship (to Y. Tang; any opinions, findings, and conclusions expressed in this material are those of the authors and do not neces-sarily reflect those of the Pelotonia Fellowship Program or The Ohio State University), and a postdoctoral fellowship from the American Heart Association (to D.E. Ochayon). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85122158176&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-20-0833
DO - 10.1158/2159-8290.CD-20-0833
M3 - Article
C2 - 34193438
AN - SCOPUS:85122158176
VL - 11
SP - 3142
EP - 3157
JO - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 12
ER -
