GPR182 limits antitumor immunity via chemokine scavenging in mouse melanoma models

Robert J. Torphy, Yi Sun, Ronggui Lin, Alayna Caffrey-Carr, Yuki Fujiwara, Felix Ho, Emily N. Miller, Martin D. McCarter, Traci R. Lyons, Richard D. Schulick, Ross M. Kedl and Yuwen Zhu ()
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Robert J. Torphy: University of Colorado Anschutz Medical Campus
Yi Sun: University of Colorado Anschutz Medical Campus
Ronggui Lin: University of Colorado Anschutz Medical Campus
Alayna Caffrey-Carr: University of Colorado Anschutz Medical Campus
Yuki Fujiwara: University of Colorado Anschutz Medical Campus
Felix Ho: University of Colorado Anschutz Medical Campus
Emily N. Miller: University of Colorado Anschutz Medical Campus
Martin D. McCarter: University of Colorado Anschutz Medical Campus
Traci R. Lyons: University of Colorado Anschutz Medical Campus
Richard D. Schulick: University of Colorado Anschutz Medical Campus
Ross M. Kedl: University of Colorado Anschutz Medical Campus
Yuwen Zhu: University of Colorado Anschutz Medical Campus

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract For many solid tumors, immune checkpoint blockade therapy has become first line treatment, yet a large proportion of patients with immunologically cold tumors do not benefit due to the paucity of tumor infiltrating lymphocytes. Here we show that the orphan G Protein-Coupled Receptor 182 (GPR182) contributes to immunotherapy resistance in cancer via scavenging chemokines that are important for lymphocyte recruitment to tumors. GPR182 is primarily upregulated in melanoma-associated lymphatic endothelial cells (LECs) during tumorigenesis, and this atypical chemokine receptor endocytoses chemokines promiscuously. In GPR182-deficient mice, T cell infiltration into transplanted melanomas increases, leading to enhanced effector T cell function and improved antitumor immunity. Ablation of GPR182 leads to increased intratumoral concentrations of multiple chemokines and thereby sensitizes poorly immunogenic tumors to immune checkpoint blockade and adoptive cellular therapies. CXCR3 blockade reverses the improved antitumor immunity and T cell infiltration characteristic of GPR182-deficient mice. Our study thus identifies GPR182 as an upstream regulator of the CXCL9/CXCL10/CXCR3 axis that limits antitumor immunity and as a potential therapeutic target in immunologically cold tumors.

Date: 2022
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DOI: 10.1038/s41467-021-27658-x

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