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：
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
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/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

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细胞的治疗癌症的免疫疗法在许多患者的诊所表现出了良好的希望，但是，仍然存在阻碍这些疗法发挥全部潜力的障碍。增强T细胞的策略肿瘤内有必要浸润，持久性和效应子功能，因为免疫抑制，敌对肿瘤微环境（TME）的性质可抑制免疫反应。细胞外腺苷三磷酸（EATP）是TME的主要组成部分，对肿瘤和免疫细胞具有不同的影响浸润肿瘤。 P2RX7是参与EATP敏感的Puringer受体，以其在其中的作用而闻名 “危险信号”识别，触发免疫细胞激活，在某些情况下是细胞死亡。我们的实验室有据报道，P2RX7 EATP-SEMSING对于记忆CD8+ T细胞分化，维护和功能是由于其在促进线粒体健康中的重要作用。这促使我们调查了是否 P2RX7对CD8+ T细胞代谢适应性的有益影响适用于CD8+ T细胞反应肿瘤免疫疗法。我们的初步数据表明P2RX7缺陷CD8+ T细胞无法有效控制黑色素瘤肿瘤，与肿瘤部位内的P2RX7 - / - CD8+ T细胞相关，异常与T细胞耗尽相关的标记表达增加。这些数据表明p2rx7是对于CD8+ T细胞肿瘤免疫呼吸剂很重要。但是，还知道P2RX7过度刺激非常高的EATP浓度（例如TME中的浓度）导致淋巴细胞死亡，这表明P2RX7 最终可能成为供体T细胞生存和整体肿瘤控制的责任。因此，我们假设初始P2RX7信号对于启动有效的CD8+ T细胞响应很重要允许在肿瘤内维持和功能。此外，我们假设我们可以通过在不同时间在不同时间更改P2RX7信号传导来增强CD8+ T细胞活性。抗肿瘤免疫反应。这些假设将在以下特定目的中进行检验：（1）确定P2RX7激活在CD8+ T细胞浸润，持续性和功能中的作用，（2）药理学P2RX7激动剂/拮抗对CD8+ T细胞抗肿瘤活性的影响。结果该建议将有助于阐明P2RX7在CD8+ T细胞肿瘤免疫中的复杂作用，并将告知 P2RX7是否可以作为自适应细胞治疗方案中的一种新型治疗方法。