Melanoma Immunotherapy with GPR182 blockade
Yuwen Zhu, PhD
|Mid-Career Bridge Grant
|University of Colorado Denver
Immune checkpoint inhibitor therapy has greatly improved survival of patients with late-stage melanoma. However, about 2/3 of patients do not benefit from this therapy. One of the main hurdles is that many melanoma tissues lack effector CDS+ T cell infiltrates. Chemokines such as CXCL9 and CXCL 10 play an important role in regulating T cell infiltration into the tumors. Atypical Chemokine Receptors are a group of GPCR proteins that are expressed in non-immune cells to actively clear chemokines by endocytosis. Our studies uncovered GPR182 as a novel ACKR receptor selectively upregulated in peritumoral lymphatics. Our preliminary results indicated that ablation of this molecule in mice leads 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 will offer 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 w II be investigated. Finally, the in vivo antitumor effect of a peptide, which blocks the interaction between GPR182 and chemokines, will be optimized. 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.