{"doi":"10.1158/2159-8290.c.6549403","title":"Data from Tumor Microenvironment–Derived R-spondins Enhance Antitumor Immunity to Suppress Tumor Growth and Sensitize for Immune Checkpoint Blockade Therapy","abstract":"<div>Abstract<p>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., <i>RSPO3</i>) 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<sup>+</sup> 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.</p>Significance:<p>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.</p><p><i>This article is highlighted in the In This Issue feature, p. 2945</i></p></div>","journal":null,"year":2023,"id":406064,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9473,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":546812,"name":"Qian Xu","orcid":"0000-0003-2679-8295","position":1,"is_corresponding":false},{"id":681801,"name":"Liang Hu","orcid":"0000-0001-5559-3913","position":2,"is_corresponding":false},{"id":226804,"name":"Xiaomei Yan","orcid":"0000-0002-7482-6863","position":3,"is_corresponding":false},{"id":1184819,"name":"Xiaomin Feng","orcid":"0009-0007-2212-5268","position":4,"is_corresponding":false},{"id":712268,"name":"Asumi Yokota","orcid":null,"position":5,"is_corresponding":false},{"id":467843,"name":"Weinan Wang","orcid":"0000-0002-7280-9023","position":6,"is_corresponding":false},{"id":772506,"name":"Di Zhan","orcid":"0000-0003-3363-1899","position":7,"is_corresponding":false},{"id":521335,"name":"Durga Krishnamurthy","orcid":null,"position":8,"is_corresponding":false},{"id":521337,"name":"David E. Ochayon","orcid":null,"position":9,"is_corresponding":false},{"id":1184820,"name":"Lijun Wen","orcid":"0000-0001-6322-8780","position":10,"is_corresponding":false},{"id":987266,"name":"Li Huo","orcid":"0000-0003-1216-083X","position":11,"is_corresponding":false},{"id":1184821,"name":"Huimin Zeng","orcid":"0000-0001-7381-6236","position":12,"is_corresponding":false},{"id":1184822,"name":"Yingwan Luo","orcid":"0000-0002-4831-3941","position":13,"is_corresponding":false},{"id":872311,"name":"L. 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