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

靶向免疫 GPCR 库作为口腔癌的新型多模式癌症免疫治疗策略

• 批准号: 10610341
• 负责人: Bryan Yung
• 金额: $ 4.23万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10610341
• 关键词: ADORA2A gene; ADRB1 gene; ADRB2 gene; Address; Adenosine; Adrenergic Agents; Adrenergic Receptor; Affect; Animal Model; Antineoplastic Agents; Binding; Bioinformatics; Biology; Bypass; CD8-Positive T-Lymphocytes; CTLA4 gene; CXC chemokine receptor 3; CXCR3 gene; Cancer Center; Cancer Patient; Cell surface; Cells; Clinical; Combination immunotherapy; Coupled; Couples; Coupling; Cues; Cytotoxic T-Lymphocytes; Data; Data Set; Drug Targeting; Effectiveness; FDA approved; Family; Functional disorder; G Protein Gene; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Genes; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Homeostasis; Human; Immune; Immune Targeting; Immune system; Immunooncology; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Vitro; In complete remission; Incidence; Inflammatory; Institution; Lead; Ligands; Link; Liquid substance; Lymphocytic choriomeningitis virus; Malignant Neoplasms; Mediating; Mentorship; Metastatic/Recurrent; Modeling; Mus; Neurotransmitters; Oncology; Outcome; PTGS2 gene; Patients; Pharmaceutical Preparations; Phase; Physiological Processes; Play; Population; Prognosis; Prostaglandins; Research; Resistance; Role; Scientist; Signal Pathway; Signal Transduction; Solid; Surface; Survival Rate; T-Lymphocyte; Techniques; Tobacco; Training; Tumor Immunity; Tumor-infiltrating immune cells; Up-Regulation; Writing; anti-tumor immune response; cancer immunotherapy; cancer infiltrating T cells; cancer therapy; career; cell motility; checkpoint receptors; chemokine; chemokine receptor; computational pipelines; cytotoxic; cytotoxicity; desensitization; design; designer receptors exclusively activated by designer drugs; exhaust; exhaustion; genetic approach; immune cell infiltrate; immune checkpoint; immune checkpoint blockade; in vivo; malignant mouth neoplasm; migration; mouse model; multimodality; neglect; next generation; novel; novel strategies; personalized immunotherapy; pharmacologic; programmed cell death protein 1; receptor; response; skill acquisition; standard of care; transcriptome sequencing; transcriptomics; transgene expression; translational oncology; transmission process; tumor; tumor microenvironment; tumor-immune system interactions

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.

抽象的 免疫检查点阻断（ICB）抑制程序性死亡-1（PD-1）和细胞毒性T-的最新进展 淋巴细胞抗原 4 (CTLA-4) 彻底改变了癌症治疗的护理标准。 头颈鳞状细胞癌 (HNSCC) 的有限缓解率表明，新方法和 显然需要靶点来充分阐明功能失调和耗尽的 CD8 T 细胞的潜在生物学原理 G 蛋白偶联受体 (GPCR) 是最有效的。 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 在这里，我们计划针对已确定的 GPCR。 使用 RNAseq 检测功能失调的 T 细胞以缓解 HNSCC 中的免疫抑制肿瘤微环境。 初步数据显示，激活的 Gαs 偶联受体 PTGER2、PTGER4 和 ADRB2 上调 HNSCC 患者中 T 细胞耗尽，表明这些 GPCR 与 G 蛋白 Gαs 偶联， 它们的下游信号级联可能会抑制 CD8 T 细胞的抗肿瘤细胞毒性，从而导致 我们的中心假设是肿瘤中炎症和β-肾上腺素配体的分泌。 微环境及其对 CD8 T 细胞的作用导致 Gαs 信号传导和 T 细胞功能障碍，从而降低 Gαs 偶联的 GPCR 可能具有细胞毒性和迁移活性，从而使 ICB 的有效性失效。 作为免疫检查点的候选者，可以与 ICB 结合作为新颖的一部分 使用多模式精准免疫疗法来激活免疫系统以摧毁肿瘤。 生物信息学、化学遗传学方法和可转化动物模型，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 Gαs 偶联受体作为增强现有功能的手段 免疫疗法可为 HNSCC 患者带来良好的结果。 拟议的研究将在加州大学圣地亚哥分校摩尔斯癌症中心进行，该中心位于癌症研究的最前沿。 该申请详细介绍了申请人的培训计划，包括研究指导、 高级课程、新技术培训以及科学专业精神、写作、 本申请中概述的研究和培训将使申请人做好准备。 作为一名独立科学家从事学术研究。