UC San Diego

Cancer immunotherapy has brought about a paradigm shift in the standard of care for cancer patients; however, the limited response rates in cancer patients underscores the persistent challenge in translating preclinical findings to effective clinical interventions. Here, we explore the imperative of 1) refining and developing preclinical animal models to better mirror human cancer and 2) identifying G protein-coupled receptors (GPCRs) as a promising avenue to improving responses to immunotherapy. Clinical success in the discovery and development of anti-cancer drugs have relied on the use of preclinical animal models, namely mice, to recapitulate tumor growth kinetics and tumor-intrinsic elements of human disease. However, many of the most commonly used syngeneic models for cancer immunotherapy do not properly resemble the disease state for which they were designed, and this discrepancy has been associated with a high attrition rate of preclinical and early-stage drug candidates failing to gain Food and Drug Administration (FDA) approval. This underscores the need to validate pre-existing models for disease relevance as well as to develop new pre-clinical models that can translate to human responses. Using new and pre-existing preclinical models, our research has identified GPCRs as critical regulators of the immune response within the tumor microenvironment (TME). 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 target GPCRs that have been identified on dysfunctional T cells using RNA-seq to relieve the immunosuppressive tumor microenvironment. Preliminary data shows an upregulation of Gαs-coupled receptors, PTGER2, PTGER4, and ADRB2, on activated and exhausted T cells in HNSC 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 T cell dysfunction and exhaustion.