Targeting the immune GPCR repertoire as a novel multimodal cancer immunotherapy strategy in oral cancer

摘要

ABSTRACT Recent advances in immune checkpoint blockade (ICB) inhibiting programmed death-1 (PD-1) and cytotoxic T- lymphocyte antigen-4 (CTLA-4) have revolutionized the standard of care for cancer treatment. However, the limited response rates in head and neck squamous cell carcinomas (HNSCC) suggest that new approaches and targets are clearly needed to fully elucidate the underlying biology of dysfunctional and exhausted CD8 T cells in cancer and achieve durable responses (cure). 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. Here, we plan to target GPCRs that have been identified on dysfunctional T cells using RNAseq to relieve the immunosuppressive tumor microenvironment in HNSCC. Preliminary data shows an upregulation of Gαs-coupled receptors, PTGER2, PTGER4, and ADRB2, on activated and exhausted T cells in HNSCC patients, suggesting that these GPCRs that are coupled to the G protein Gαs, and their downstream signaling cascades may be dampening anti-tumor cytotoxicity of CD8 T cells, leading to exhaustion. Our central hypothesis is that secretion of inflammatory and beta-adrenergic ligands in the tumor microenvironment and their actions on CD8 T cells lead to Gαs signaling and T cell dysfunction, which decreases cytotoxic and migratory activity that nullifies the effectiveness of ICB. Altogether, Gαs-coupled GPCRs may represent candidates as immune checkpoints that can be targeted in combination with ICB as part of novel multimodal precision immunotherapy approaches to reactive the immune system to destroy tumors. Using bioinformatics, chemogenetic approaches, and translatable animal models, we aim to elucidate the role of Gαs signaling in T cell dysfunction and to target endogenous Gαs-coupled receptors as a means to enhance existing immunotherapies to generate favorable outcomes in HNSCC patients. The proposed research will be conducted at UCSD’s Moores Cancer Center, an institution at the forefront of translational oncology. This application details the applicant’s training plan including research mentorship, advanced coursework, training in new techniques, and development of skills in scientific professionalism, writing, and presentation of data. The research and training outlined in this application will prepare the applicant to pursue a career in the conduct of academic research as an independent scientist.