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

摘要 免疫检查点阻断（ICB）抑制程序性死亡-1（PD-1）和细胞毒性T细胞的最新进展 淋巴细胞抗原-4（CTLA-4）已经彻底改变了癌症治疗的护理标准。但 头颈部鳞状细胞癌（HNSCC）有限的反应率表明，新的方法和 明确需要靶点来充分阐明功能失调和衰竭的CD 8 T细胞的潜在生物学 并实现持久的反应（治愈）。G蛋白偶联受体（GPCR）是最强烈的 研究药物靶点，因为它们在许多生理过程中发挥关键作用，并且它们仍然存在 长期有利的药理学靶点。在这里，我们计划针对已经在 使用RNAseq来缓解HNSCC中的免疫抑制性肿瘤微环境。 初步数据显示，Gα s偶联受体PTGER 2、PTGER 4和ADRB 2在活化的 HNSCC患者的T细胞耗竭，这表明这些与G蛋白Gα偶联的GPCR， 它们的下游信号级联可能抑制CD 8 T细胞的抗肿瘤细胞毒性，导致 疲惫不堪我们的中心假设是肿瘤中炎症和β-肾上腺素能配体的分泌 微环境及其对CD 8 T细胞的作用导致Gαs信号传导和T细胞功能障碍， 细胞毒性和迁移活性，使ICB的有效性无效。总之，Gα s偶联的GPCR可能 将候选物表示为免疫检查点，其可以与ICB组合靶向，作为新的免疫检查点的一部分。 多模式精确免疫治疗方法使免疫系统反应以破坏肿瘤。使用 生物信息学、化学遗传学方法和可翻译的动物模型，我们的目标是阐明Gαs的作用 T细胞功能障碍中的信号传导，并靶向内源性Gα s偶联受体作为增强现有 免疫疗法在HNSCC患者中产生有利的结果。 这项拟议中的研究将在加州大学圣地亚哥分校的摩尔癌症中心进行，该中心是一个处于最前沿的机构。 转化肿瘤学此申请详细说明了申请人的培训计划，包括研究导师， 高级课程，新技术培训，科学专业技能的发展，写作， 和数据的呈现。本申请中概述的研究和培训将使申请人做好准备， 作为一名独立的科学家从事学术研究。

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.