Related Experiment Video
Updated: Oct 7, 2025
Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
GPR182 limits antitumor immunity via chemokine scavenging in mouse melanoma models
Robert J Torphy1, Yi Sun1, Ronggui Lin1
1Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
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.
Insights
The orphan G Protein-Coupled Receptor 182 (GPR182) limits anti-tumor immunity by scavenging chemokines essential for T cell recruitment. Inhibiting GPR182 enhances T cell infiltration and immunotherapy effectiveness in cold tumors.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Immune checkpoint blockade therapy is a first-line treatment for many solid tumors.
- A significant portion of patients with immunologically cold tumors do not benefit from this therapy due to a lack of tumor-infiltrating lymphocytes.
- Understanding mechanisms of immunotherapy resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the role of the orphan G Protein-Coupled Receptor 182 (GPR182) in cancer immunotherapy resistance.
- To determine if GPR182 contributes to the "immunologically cold" tumor phenotype.
- To explore GPR182 as a potential therapeutic target for enhancing anti-tumor immunity.
Main Methods:
- Studied GPR182 expression in melanoma-associated lymphatic endothelial cells (LECs) during tumorigenesis.
- Utilized GPR182-deficient mouse models with transplanted melanomas.
- Assessed T cell infiltration, effector T cell function, and anti-tumor immunity in GPR182-deficient versus wild-type mice.
- Investigated the effect of CXCR3 blockade on anti-tumor immunity in GPR182-deficient mice.
Main Results:
- GPR182 is upregulated in melanoma-associated LECs and promiscuously endocytoses chemokines.
- GPR182 deficiency led to increased T cell infiltration into melanomas.
- Ablation of GPR182 increased intratumoral chemokine concentrations, enhancing effector T cell function and anti-tumor immunity.
- GPR182 deficiency sensitized poorly immunogenic tumors to immune checkpoint blockade and adoptive cellular therapies.
- CXCR3 blockade reversed the enhanced anti-tumor immunity and T cell infiltration observed in GPR182-deficient mice.
Conclusions:
- GPR182 acts as an upstream regulator of the CXCL9/CXCL10/CXCR3 axis, limiting anti-tumor immunity.
- GPR182 contributes to immunotherapy resistance in "immunologically cold" tumors.
- Targeting GPR182 presents a potential therapeutic strategy to improve responses to cancer immunotherapies.
