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。

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要基于 T 细胞的癌症免疫疗法在临床上对许多患者显示出卓越的前景，但仍然存在阻碍这些疗法充分发挥 T 细胞潜力的障碍。肿瘤内的浸润、持久性和效应功能是必要的，因为免疫抑制、敌意肿瘤微环境（TME）的性质会抑制细胞外腺苷的免疫反应。三磷酸盐 (eATP) 是 TME 的主要成分，对肿瘤和免疫细胞有不同的影响 P2RX7 是一种参与 eATP 感应的嘌呤受体，以其在肿瘤中的作用而闻名。 “危险信号”识别，触发免疫细胞激活，在某些情况下，甚至引发细胞死亡。报道称，P2RX7 eATP 感应对于记忆 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，这促使我们研究是否具有这种功能。 P2RX7 对 CD8+ T 细胞代谢适应性的有益影响将适用于 CD8+ T 细胞反应我们的初步数据表明，P2RX7 缺陷的 CD8+ T 细胞无法有效地治疗肿瘤。控制黑色素瘤，与肿瘤部位内较少的 P2rx7-/- CD8+ T 细胞和异常相关与 T 细胞耗竭相关的标记物的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，但也已知 P2RX7 过度刺激。非常高的 eATP 浓度（例如 TME 中的 eATP 浓度）会导致淋巴细胞死亡，表明 P2RX7 可能最终成为供体 T 细胞存活和整体肿瘤控制的负担。初始 P2RX7 信号传导对于启动有效的 CD8+ T 细胞反应非常重要允许 T 细胞在肿瘤内维持和发挥功能。可以通过在不同时间改变 P2RX7 信号传导来增强 CD8+ T 细胞活性这些假设将在以下具体目标中得到检验：（1）确定 P2RX7 激活在肿瘤内 CD8+ T 细胞浸润、持久性和功能中的作用，以及 (2) 药理 P2RX7 激动/拮抗作用对 CD8+ T 细胞抗肿瘤活性的影响。该提案将有助于阐明 P2RX7 在 CD8+ T 细胞肿瘤免疫中的复杂作用，并为 P2RX7 是否可以作为过继细胞治疗方案中的一种新型治疗方法。