General Surgery Resident University of Colorado Denver, Colorado, United States
Disclosure: Disclosure information not submitted.
Participants should be aware of the following financial/non-financial relationships:
Robert J. Torphy, MD PhD: Disclosure information not submitted.
Introduction: Converting immunologically cold tumors to inflamed tumors is essential to expand the efficacy of immunotherapy. The objective of this study is to describe the expression pattern and function of a chemokine scavenger, G Protein-Coupled Receptor 182 (GPR182), and evaluate its role as a therapeutic target in immunologically cold preclinical models of melanoma.
Methods: Single cell expression data and primary human tissue samples were analyzed to determine the expression pattern of GPR182 in human melanoma. GPR182 deficient mice were used to evaluate the effect of GPR182 on tumor growth, T cell homing, and sensitization to immunotherapy in B16 and YUMM1.7 melanoma models. Tumor infiltrating lymphocytes (TILs) and intratumoral chemokine levels were evaluated from harvested tumor tissue using flow cytometry.
Results: GPR182 is selectively upregulated in melanoma-associated lymphatic endothelial cells (LECs) compared to adjacent normal skin. GPR182-deficient mice exhibit enhanced antitumor immunity in multiple preclinical melanoma models with reduced tumor outgrowth that was reversed with CD4+ and CD8+ T cell depletion. Tumors from GPR182-deficient mice exhibited increased T cell infiltration and effector T cell function in the tumor microenvironment. Loss of GPR182 resulted in increased intratumoral concentrations of proinflammatory chemokines CXCL9 and CXCL10. Wild type (WT) and GPR182 deficient mice harboring immunologically cold B16 or YUMM1.7 tumors were treated with single agent (anti-PD1) or dual immune checkpoint blockade (anti-CTLA-4 and anti-PD1), respectively. WT tumors were unresponsive to immunotherapy; however, GPR182 deficient mice exhibited a significant reduction in tumor growth and had a prolonged overall survival in both preclinical models.
Conclusions: Our study identifies lymphatic endothelial GPR182 as a brake to limit antitumor immunity by scavenging pro-inflammatory chemokines and suppressing effector T cell homing into the tumor microenvironment. GPR182 is a therapeutic target for immunologically cold tumors as GPR182 ablation sensitizes immunologically cold tumors to immunotherapy.
Learning Objectives:
Understand the barriers of immunotherapy in immunologically cold tumors.
Understand the role of lymphatic endothelial cells in limiting antitumor immunity.
Understand the role of therapeutically targeting GPR182 in immunologically cold tumors.