Data from Tumor Microenvironment–Derived R-spondins Enhance Antitumor Immunity to Suppress Tumor Growth and Sensitize for Immune Checkpoint Blockade Therapy Article Swipe

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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 , Éric Vivier , Jianfeng Zhou , Stephen N. Waggoner , Gang Huang ·

YOU? · · 2023 · Open Access · · DOI: https://doi.org/10.1158/2159-8290.c.6549403.v1

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

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Tumor microenvironment Cancer research Immune checkpoint Cytotoxic T cell Immune system Biology CD8 Wnt signaling pathway Immunology Immunotherapy Cell biology Signal transduction In vitro Biochemistry

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Type: preprint
Language: en
Landing Page: https://doi.org/10.1158/2159-8290.c.6549403.v1
OA Status: gold
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DOI: https://doi.org/10.1158/2159-8290.c.6549403.v1

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Title: Data from Tumor Microenvironment–Derived R-spondins Enhance Antitumor Immunity to Suppress Tumor Growth and Sensitize for Immune Checkpoint Blockade Therapy

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Type: preprint

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Language: en

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Publication year: 2023

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Publication date: 2023-04-03

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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, Éric Vivier, Jianfeng Zhou, Stephen N. Waggoner, Gang Huang

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Landing page: https://doi.org/10.1158/2159-8290.c.6549403.v1

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Concepts: Tumor microenvironment, Cancer research, Immune checkpoint, Cytotoxic T cell, Immune system, Biology, CD8, Wnt signaling pathway, Immunology, Immunotherapy, Cell biology, Signal transduction, In vitro, Biochemistry

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abstract_inverted_index.putative	198
abstract_inverted_index.receptor	76
abstract_inverted_index.therapy,	150
abstract_inverted_index.Exogenous	83
abstract_inverted_index.R-spondin	33, 63, 74, 89, 118, 128, 142
abstract_inverted_index.antitumor	11, 162
abstract_inverted_index.cytotoxic	99
abstract_inverted_index.effectors	9
abstract_inverted_index.enhancing	161
abstract_inverted_index.favorable	40
abstract_inverted_index.injection	87
abstract_inverted_index.prognosis	41
abstract_inverted_index.rationale	172
abstract_inverted_index.responses	13
abstract_inverted_index.ribosomal	139
abstract_inverted_index.signaling	31
abstract_inverted_index.anticancer	189
abstract_inverted_index.associated	38
abstract_inverted_index.checkpoint	18, 167
abstract_inverted_index.correlates	44
abstract_inverted_index.developing	174
abstract_inverted_index.expression	28, 84, 144
abstract_inverted_index.identifies	157
abstract_inverted_index.intratumor	86
abstract_inverted_index.modulation	187
abstract_inverted_index.positively	43
abstract_inverted_index.regulating	202
abstract_inverted_index.signatures	47
abstract_inverted_index.3–induced	119
abstract_inverted_index.anti–PD-1	149
abstract_inverted_index.biogenesis.	140
abstract_inverted_index.contributed	116
abstract_inverted_index.endothelial	56
abstract_inverted_index.fibroblasts	60
abstract_inverted_index.highlighted	207
abstract_inverted_index.inhibition,	168
abstract_inverted_index.inhibitors.	19
abstract_inverted_index.mechanistic	182
abstract_inverted_index.potentiator	32
abstract_inverted_index.regression.	106
abstract_inverted_index.sensitivity	147
abstract_inverted_index.sensitizing	165
abstract_inverted_index.therapeutic	154
abstract_inverted_index.Importantly,	141
abstract_inverted_index.highlighting	152
abstract_inverted_index.implications	195
abstract_inverted_index.infiltration	95
abstract_inverted_index.upregulation	135
abstract_inverted_index.3–producing	64
abstract_inverted_index.cooperatively	115
abstract_inverted_index.independently	113
abstract_inverted_index.correspondingly	71
abstract_inverted_index.immunotherapies	176
abstract_inverted_index.R-spondin–LGR6	199
abstract_inverted_index.microenvironment	81
abstract_inverted_index.cancer-associated	59
abstract_inverted_index.signaling–mediated	186
abstract_inverted_index.<i>RSPO3</i>)	36
abstract_inverted_index.CD8<sup>+</sup>	110
abstract_inverted_index.<div>Abstract<p>Natural	0
abstract_inverted_index.2945</i></p></div>	215
abstract_inverted_index.biology.</p><p><i>This	204
abstract_inverted_index.avenues.</p>Significance:<p>Our	155
cited_by_percentile_year
countries_distinct_count	0
institutions_distinct_count	21
citation_normalized_percentile.value	0.21066889
citation_normalized_percentile.is_in_top_1_percent	False
citation_normalized_percentile.is_in_top_10_percent	False