Illuminating the onco-GPCRome: targeting the prostaglandin receptor-Gαs signaling axis as a novel immune checkpoint in cancer

Abstract

Abstract Recent advances in checkpoint blockade immunotherapy (CBI) have revolutionized cancer treatment, but the limited response rates in most cancers suggest that new approaches and targets are clearly needed to fully elucidate the underlying biology of dysfunctional CD8 T cells and achieve durable responses. G-protein coupled receptors (GPCRs) are the most intensively studied drug targets as they play key roles in many physiological processes, and they have remained longstanding favorable pharmacological targets. Using novel computational approaches integrating multiple single cell RNAseq databases, we first deconvoluted tumor-infiltrating T cell heterogeneity to generate a transcriptomic GPCR signature based on coupling specificity and receptor family. Preliminary data shows an upregulation of prostaglandin receptors, PTGER2 and PTGER4, on exhausted T cells, suggesting that these GPCRs, coupled to the Gαs G protein α subunit, may contribute to diminishing anti-tumor cytotoxicity. Expression and stimulation of EP2 and EP4 on highly activated CD8 T cells and subsequent Gαs signaling decreases cytokine secretion and CXCR3-mediated migration. Additionally, blockade of EP2 and EP4 significantly decreases tumor growth in multiple immune competent, syngeneic tumor models. Altogether, we hypothesize that activation of Gαs downstream signaling cascades may be dampening the anti-tumor cytotoxicity of CD8 T cells, thereby limiting the effectiveness of PD-1 and CTLA-4 blockade. EP2 and EP4 and Gαs signaling may represent promising candidates as immune checkpoints that can be targeted in combination with CBI as part of novel multimodality precision immunotherapy approaches to reactivate the immune system to destroy tumors.