Melanoma Immunotherapy with GPR182 blockade

Project Summary Melanoma immunotherapy with GPR182 blockade Immune checkpoint inhibitor therapy has greatly improved survival of patients with late-stage melanoma. However, over half of patients do not benefit from this therapy. One of the main hurdles is that many melanoma tissues lack effector CD8+ T cell infiltrates. Chemokines such as CXCL9 and CXCL10 play an important role in regulating effector T cell infiltration into the tumors. Atypical Chemokine Receptors are a group of GPCR proteins that are expressed in non-immune cells to actively regulate chemokines by endocytosis. Our studies uncovered GPR182 as a novel ACKR receptor selectively upregulated in peritumoral lymphatics. Our preliminary results indicated that genetic deletion of this molecule in mice led to increased effector T cell infiltration and thereby the retardment of tumor growth in several mouse melanoma models. We further found that GPR182 interacts with chemokines broadly in vitro and blockade of CXCR3 completely abolished improved antitumor immunity in GPR182- deficient mice. Here we hypothesize that GPR182 inhibits anti-tumor immune response by limiting chemokine availability and targeting this pathway offers a novel approach to converting immunologically cold melanoma to hot ones. We will dissect the molecular interaction between GPR182 and chemokines, and also examine the chemokine endocytosis by GPR182 with tumors. The mechanisms by which GPR182 inhibits antitumor T cell response will be investigated. Finally, the in vivo antitumor effect of a GPR182 monoclonal antibody, which blocks the interaction between GPR182 and chemokines, will be assessed. By the completion of these studies, we will identify a new strategy of inflaming immunologically cold melanoma and will have a better understanding of the immunomodulatory role of the lymphatics in melanoma.