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GPCRs as Next-Gen Targets for Immune Oncology

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Abstract

G-protein coupled receptors (GPCRs) are the most intensively studied drug targets since they play key roles in many physiological processes, and they have remained longstanding favorable pharmacological targets. GPCRs have become one of the top targets for pharmaceutical drug development, largely due to their known dysregulated expression and aberrant functions in some of the most prevalent human diseases. However, the study of the role of GPCRs in tumor biology has only just begun to make headway. Though recent advances have enriched our understanding of the contribution of GPCRs to tumorigenesis, angiogenesis, and immune evasion, drug development for GPCRs in oncology is still underexploited. Adding to his, although checkpoint blockade immunotherapies (CBI) inhibiting programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) have revolutionized cancer treatment, the limited response rates in most cancers suggest that new approaches, targets, and animal models that more faithfully recapitulate human cancers are clearly needed to fully elucidate the underlying biology of resistance to cancer immunotherapies. Here, we first developed a full, comprehensive analysis of GPCRs across multiple tumor types to highlight GPCRs that may be important to target on the global tumor level. Next, we explored whether a carcinogen-induced mouse model of oral cancer can better model mutational signatures and response to immunotherapies of human head and neck cancers. With these novel tools and analyses, we aimed to uncover new GPCR targets for immune oncology with cutting edge chemogenetic approaches to investigate the role of downstream Gas-signaling in CD8 T cells that infiltrate tumors. Altogether, our work here provides a platform to identify emerging GPCR targets that when blocked concomitant with PD-1 and CTLA-4, can enable achieving a higher response rate and more durable responses (cure). Ultimately, our studies provide novel therapeutic interventions as part of multimodal precision immunotherapies for oncology

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This item is under embargo until December 17, 2023.