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: 10661581
• 负责人: Kelsey Wanhainen
• 金额: $ 5.27万
• 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/10661581
• 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; Immunologic Stimulation; Impairment; In Vitro; Individual; Infiltration; 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; Physicians; Production; Purinoceptor; Regimen; Reporting; Research Personnel; Role; Signal Transduction; Site; Specificity; Supporting Cell; T cell differentiation; T cell infiltration; T cell response; T cell therapy; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Treatment Efficacy; Tumor Immunity; Tumor Promotion; 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; pharmacologic; 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 用于治疗癌症的基于T细胞的免疫疗法在临床上对许多患者显示出出色的前景， 但是仍然存在阻碍这些疗法充分发挥潜力的障碍。增强T细胞免疫的策略 肿瘤内的浸润、持久性和效应器功能是必要的，因为免疫抑制剂、敌对性免疫抑制剂、 肿瘤微环境（TME）的性质起到抑制免疫应答的作用。细胞外腺苷 三磷酸（eATP）是TME的主要成分，对肿瘤和免疫细胞具有不同的作用 浸润肿瘤P2 RX 7是一种参与eATP传感的嘌呤受体，最为人所知的是其在 “危险信号”识别，触发免疫细胞激活，在某些情况下，触发细胞死亡。我们的实验室 报道，P2 RX 7 eATP传感对于记忆性CD 8 + T细胞分化、维持和分化是必需的。 由于其在促进线粒体健康方面的重要作用，因此具有重要的功能。这让我们开始调查 P2 RX 7对CD 8 + T细胞代谢适应性的有益作用将适用于CD 8 + T细胞应答， 肿瘤免疫治疗我们的初步数据表明，P2 RX 7缺陷型CD 8 + T细胞不能有效地抑制CD 8 + T细胞的增殖。 对照黑色素瘤肿瘤，与肿瘤部位内较少的P2 rx 7-/-CD 8 + T细胞和异常的 与T细胞耗竭相关的标志物表达增加。这些数据表明P2 RX 7是 对于CD 8 + T细胞肿瘤免疫应答很重要。然而，还已知P2 RX 7过度刺激， 非常高的eATP浓度，如TME中的浓度，导致淋巴细胞死亡，表明P2 RX 7 可能最终成为供体T细胞存活和整体肿瘤控制的负担。所以我们 假设初始P2 RX 7信号传导对于引发有效的CD 8 + T细胞应答是重要的 允许T细胞在肿瘤内维持和发挥功能。此外，我们假设， 可以通过改变P2 RX 7信号转导途径在不同时间增强CD 8 + 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进行检验：（1） 确定P2 RX 7活化在肿瘤内的CD 8 + T细胞浸润、持久性和功能中的作用，以及（2） 药理学P2 RX 7激动/拮抗作用对CD 8 + T细胞的抗肿瘤活性的影响。的结果 这一提议将有助于阐明P2 RX 7在CD 8 + T细胞肿瘤免疫中的复杂作用， P2 RX 7是否可以作为过继性细胞治疗方案中的新治疗方法。