# Melanoma Immunotherapy with GPR182 blockade

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $337,922

## Abstract

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.

## Key facts

- **NIH application ID:** 10749045
- **Project number:** 5R01CA269644-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Yuwen Zhu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $337,922
- **Award type:** 5
- **Project period:** 2023-01-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10749045

## Citation

> US National Institutes of Health, RePORTER application 10749045, Melanoma Immunotherapy with GPR182 blockade (5R01CA269644-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10749045. Licensed CC0.

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