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.
© 2022. The Author(s).
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Movement
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Chemokine CXCL10 / genetics*
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Chemokine CXCL10 / immunology
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Chemokine CXCL9 / genetics*
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Chemokine CXCL9 / immunology
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Gene Expression Regulation, Neoplastic
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Humans
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Immunotherapy / methods
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Lymphocytes, Tumor-Infiltrating / cytology
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Lymphocytes, Tumor-Infiltrating / immunology
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Melanoma / genetics*
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Melanoma / immunology
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Melanoma / mortality
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Melanoma / therapy
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Melanoma, Experimental / genetics*
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Melanoma, Experimental / immunology
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Melanoma, Experimental / mortality
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Melanoma, Experimental / therapy
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Mice
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Mice, Knockout
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Protein Binding
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Receptors, CXCR3 / genetics*
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Receptors, CXCR3 / immunology
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Receptors, G-Protein-Coupled / genetics*
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Receptors, G-Protein-Coupled / immunology
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Signal Transduction
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Skin Neoplasms / genetics*
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Skin Neoplasms / immunology
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Skin Neoplasms / mortality
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Skin Neoplasms / therapy
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Survival Analysis
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T-Lymphocytes, Cytotoxic / cytology
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / transplantation
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Tumor Burden
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Tumor Microenvironment / genetics
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Tumor Microenvironment / immunology
Substances
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CXCL10 protein, human
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CXCL9 protein, human
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CXCR3 protein, human
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Chemokine CXCL10
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Chemokine CXCL9
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GPR182 protein, human
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Receptors, CXCR3
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Receptors, G-Protein-Coupled