Role of P2RX7 in making CD8+ T cells for tumor immunotherapy.

P2RX7 在制造用于肿瘤免疫治疗的 CD8 T 细胞中的作用。

• 批准号: 10452483
• 负责人: Kelsey Wanhainen
• 金额: $ 3.4万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452483
• 关键词: Ablation; Adenosine Triphosphate; Adoptive Cell Transfers; Agonist; Antitumor Response; CD8-Positive T-Lymphocytes; Cancer Control; Cell Death; Cell Maintenance; Cell Survival; Cell physiology; Cells; Cellular Stress; Cellular immunotherapy; Cessation of life; Chronic; Clinic; Data; Exhibits; Functional disorder; Future; Generations; Genes; Genetic; Granzyme; Harvest; Health; Immune; Immune response; Immune system; Impairment; In Vitro; Individual; Interferon Type II; Longevity; Lymphocyte; Maintenance; Malignant Neoplasms; Mediating; Membrane Potentials; Memory; Metabolic; Mitochondria; Modeling; Mus; Nature; Normal tissue morphology; Oncology; Oxidative Phosphorylation; Pathway interactions; Patients; Pharmacology; Physicians; Production; Purinoceptor; Regimen; Reporting; Research Personnel; Role; Signal Transduction; Site; Specificity; Supporting Cell; T cell differentiation; T cell response; T cell therapy; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Treatment Efficacy; Tumor Immunity; Tumor-infiltrating immune cells; Virus Diseases; aerobic glycolysis; antagonist; anti-tumor immune response; cancer therapy; career; cell injury; cytokine; effector T cell; exhaustion; experimental study; extracellular; fitness; immune activation; immune checkpoint blockade; improved; in vivo; insight; melanoma; metabolic fitness; neoplasm immunotherapy; neoplastic cell; novel; novel therapeutic intervention; prevent; receptor; response; skills; therapeutic target; tumor; tumor growth; tumor immunology; tumor metabolism; tumor microenvironment; tumor-immune system interactions

Project Abstract T cell-based immunotherapies to treat cancer have shown outstanding promise in the clinic for many patients, but there are still barriers hindering these therapies from reaching full potential. Strategies to enhance T cell infiltration, persistence and effector function within the tumor are necessary, as the immunosuppressive, hostile nature of the tumor microenvironment (TME) serves to dampen immune responses. Extracellular adenosine triphosphate (eATP) is a major component of the TME and has varying effects on the tumor and immune cells infiltrating the tumor. P2RX7 is a puringeric receptor involved in eATP-sensing and is best known for its role in “danger signal” recognition, triggering immune cell activation and, in some scenarios, cell death. Our lab has reported that P2RX7 eATP-sensing is essential for memory CD8+ T cell differentiation, maintenance and function due to its important role in promoting mitochondrial health. This led us to investigate whether the beneficial effects of P2RX7 on CD8+ T cell metabolic fitness would be applicable to CD8+ T cell responses in tumor immunotherapy. Our preliminary data demonstrated that P2RX7 deficient CD8+ T cells fail to effectively control melanoma tumors, correlating with fewer P2rx7-/- CD8+ T cells within the tumor site and aberrant increased expression of markers associated with T cell exhaustion. These data indicated that P2RX7 was important for CD8+ T cell tumor immune responses. However, it is also known that P2RX7 overstimulation with very high eATP concentrations, such as those in the TME, results in lymphocyte death, suggesting that P2RX7 may eventually become a liability to survival of donor T cells and overall tumor control. Therefore, we hypothesize that initial P2RX7 signaling is important for priming an effective CD8+ T cell response allowing for T cell maintenance and function within the tumor. Furthermore, we hypothesize that we can boost CD8+ T cell activity by altering P2RX7 signaling pharmacologically at different times during the anti-tumor immune response. These hypotheses will be tested in the following specific aims: (1) Determine role of P2RX7 activation in CD8+ T cell infiltration, persistence and function within tumors, and (2) Effects of pharmacological P2RX7 agonism/antagonism on anti-tumor activity of CD8+ T cells. The results of this proposal will help elucidate the complicated role of P2RX7 in CD8+ T cell tumor immunity and will inform whether P2RX7 could be targeted as a novel therapeutic approach in adoptive cell therapy regimens.

项目摘要 以T细胞为基础的免疫疗法治疗癌症在许多患者的临床上显示出突出的前景， 但仍有障碍阻碍这些疗法发挥全部潜力。增强T细胞的策略 肿瘤内的浸润性、持久性和效应器功能是必要的，因为免疫抑制、恶性 肿瘤微环境的性质(TME)可抑制免疫反应。胞外腺苷 三磷酸(EATP)是TME的主要成分，对肿瘤和免疫细胞有不同的作用 浸润性肿瘤。P2RX7是一种参与eATP传感的精氨酸受体，最为人所知的是它在 “危险信号”识别，触发免疫细胞激活，在某些情况下，细胞死亡。我们的实验室有 报道称，P2RX7 eATP传感对记忆CD8+T细胞的分化、维持和 由于其在促进线粒体健康方面的重要作用而发挥作用。这促使我们调查是否 P2RX7对CD8+T细胞代谢适合性的有利作用可能适用于CD8+T细胞反应 肿瘤免疫疗法。我们的初步数据显示，缺乏P2RX7的CD8+T细胞不能有效地 控制黑色素瘤，与肿瘤部位内P2rx7-/-CD8+T细胞减少和异常相关 与T细胞耗竭相关的标志物表达增加。这些数据表明，P2RX7是 对于CD8+T细胞肿瘤免疫反应很重要。然而，我们也知道，P2RX7过度刺激 非常高的eATP浓度，如TME中的eATP浓度，会导致淋巴细胞死亡，这表明P2RX7 最终可能成为供者T细胞存活和总体肿瘤控制的一个不利因素。因此，我们 假设初始的P2RX7信号对于启动有效的CD8+T细胞反应很重要 允许T细胞在肿瘤内维持和发挥作用。此外，我们假设我们 可通过在不同时间药理改变P2RX7信号来提高CD8+T细胞活性 抗肿瘤免疫反应。这些假设将在以下具体目标中得到检验：(1) 确定P2RX7激活在CD8+T细胞在肿瘤内的浸润、持续和功能中的作用，以及(2) 药物P2RX7激动剂/拮抗剂对CD8+T细胞抗肿瘤活性的影响结果是 这一建议将有助于阐明P2RX7在CD8+T细胞肿瘤免疫中的复杂作用，并将有助于 P2RX7是否可以作为过继细胞治疗方案中的一种新的治疗手段。