Dissecting the role of hypoxia in T cell differentiation in cancer

剖析缺氧在癌症 T 细胞分化中的作用

• 批准号: 10578000
• 负责人: Greg M. Delgoffe
• 金额: $ 61.45万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578000
• 关键词: Acetylation; Address; Angiogenesis Inhibitors; Antigens; Automobile Driving; Cell physiology; Cells; Chromatin; Chronic; Clinical Trials; Complex; Consumption; Cytotoxic T-Lymphocytes; Data; Environment; Epigenetic Process; Functional disorder; Gene Expression; Genes; Genetic Transcription; Goals; Histones; Hypoxia; Immune; Immunologic Memory; Immunology; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Vitro; Infiltration; Knowledge; Ligands; Link; Machine Learning; Malignant Neoplasms; Mediating; Metabolic; Metabolic stress; Metabolism; Metformin; Methylation; Minority; Mitochondria; Modeling; Modification; Monoclonal Antibodies; Mus; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; Oxygen; PD-1 blockade; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Proliferating; Reactive Oxygen Species; Regimen; Research Personnel; Resistance; Role; Signal Transduction; Site; Solid Neoplasm; Starvation; System; T cell differentiation; T cell infiltration; T-Lymphocyte; Tumor Immunity; angiogenesis; anti-PD-1; cancer cell; cancer immunotherapy; cancer infiltrating T cells; cancer therapy; cell type; cofactor; demethylation; epigenome; exhaust; exhaustion; experience; functional outcomes; histone methylation; histone modification; immune cell infiltrate; immune checkpoint blockade; in vivo; inhibitor; melanoma; mouse model; neoplastic cell; novel; patient subsets; programmed cell death protein 1; receptor; resistance mechanism; response; stem; stressor; success; synergism; transcription factor; transcriptional reprogramming; tumor; tumor hypoxia; tumor metabolism; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Immunotherapeutic treatments for cancer, especially the use of monoclonal antibody mediated blockade of `checkpoint' molecules like PD-1, has changed the treatment paradigm for patients with solid tumors like melanoma. However, only a subset of patients benefit from these therapies, due to several resistance mechanisms concentrated within the tumor microenvironment (TME), the site of action of cytotoxic T cells. T cells must contend with physical barriers to infiltration, immunosuppressive cell types, the expression of co- inhibitory ligands on target cells, and a harsh metabolic environment produced by cancer cells. In addition to T cell-extrinsic immunosuppression, T cells within tumors have a distinct differentiation trajectory, resulting in acquisition of an alternative, dysfunctional fate termed exhaustion. Exhausted T cells are terminally differentiated, hypofunctional upon stimulation, and possess poor capacity to proliferate, a crucial component of immune memory. We and others have shown that exhausted T cells have severe metabolic deficiencies, and that metabolic stress within the TME, most notably hypoxia exposure, potentiates differentiation towards exhaustion. In line with this, we and others have shown that melanoma patients with more oxidative, hypoxic tumors are more likely to progress on anti-PD1. Thus, the hypoxic TME and the intrinsic functional deficiency of exhausted T cells are linked. However, how hypoxia and resultant oxidative stress alter T cell differentiation remain unclear. Our hypothesis is that hypoxia exposure promotes T cell exhaustion, by driving aberrant chromatin bivalency and loss of transcription, such that hypoxia mitigation treatments will alter T cell differentiation and support increased T cell function. AIM 1: How does hypoxia drive epigenetic changes that bias T cell differentiation and function? Hypoxia drives several cellular adaptations, including transcriptional reprogramming via HIF-1α, induction of reactive oxygen species (ROS), and metabolic shifts. We will A) use in vitro systems to identify mechanisms of hypoxia contributing to altered histone methylation and bivalency in murine T cells; and B) determine contributions of hypoxia to the T cell epigenome and explore potential mitigation strategies in murine tumor models. AIM 2: How do hypoxia reducing regimens alter intratumoral T cell differentiation in melanoma patients? We and other have shown that targeting tumor cell metabolism or angiogenesis can increase the oxygen tension within tumors in both mouse models and melanoma patients. In this Aim, we will take advantage of two investigator-initiated clinical trials in melanoma utilizing metformin or axitinib in combination with anti-PD-1, and deeply explore transcriptional, epigenetic, metabolic, and functional outcomes associated with reduction of hypoxia coincident with anti-PD-1. We expect these studies to address knowledge gaps in the fields of epigenetics, immunology, and cancer immunotherapy, uncovering how tumor hypoxia can bias T cell differentiation and response to anti-PD-1, with the goal of identifying novel targets that mitigate hypoxia driven T cell exhaustion and overcome barriers to immunotherapy for cancer.

项目摘要/摘要 癌症的免疫治疗治疗，尤其是使用单克隆抗体介导的封锁 诸如PD-1之类的“检查点”分子已改变了诸如实体瘤患者之类的治疗范例 黑色素瘤。但是，由于多种阻力，只有一部分患者受益于这些疗法 肿瘤微环境（TME）的机制，细胞毒性T细胞的作用部位。 细胞必须与浸润的物理障碍，免疫抑制细胞类型，共同表达 靶细胞上的抑制性配体，以及癌细胞产生的HARMSH代谢环境。除了t 细胞 - 超支免疫抑制，肿瘤中的T细胞具有明显的分化轨迹，导致 获得替代功能失调的命运所谓的疲惫。耗尽的T细胞是终端的 刺激时分化的，功能低下，并且潜在的不良能力增殖，至关重要的成分 免疫记忆。我们和其他人表明，疲惫的T细胞具有严重的代谢缺陷， TME内的代谢压力，最著名的是缺氧，潜在的分化向 精疲力尽。与此相一致，我们和其他人表明，黑色素瘤患者具有更多的氧化性，低氧性的患者 肿瘤更有可能在抗PD1上进展。那是缺氧的TME和固有功能缺陷 耗尽的T细胞链接。然而，缺氧和产生的氧化应激如何改变T细胞分化 保持不清楚。我们的假设是，通过驾驶异常，缺氧暴露会促进T细胞耗尽 染色质双价和转录的丧失，使缺氧治疗将改变T细胞 分化和支持提高了T细胞功能。目标1：缺氧如何驱动表观遗传变化 偏差细胞分化和功能？缺氧驱动几种细胞适应，包括转录 通过HIF-1α重新编程，活性氧（ROS）的诱导和代谢转移。我们将a）使用 体外系统，以确定缺氧的机制，导致组蛋白甲基化改变和双价性 鼠T细胞； b）确定缺氧对T细胞表观基因组的贡献并探索潜力 鼠肿瘤模型中的缓解策略。 AIM 2：缺氧如何减少治疗方案改变肿瘤内T 黑色素瘤患者的细胞分化？我们和其他 在小鼠模型和黑色素瘤患者中，血管生成可以增加肿瘤内肿瘤内的氧气张力。在 这个目的，我们将利用二甲双胍或 Axitinib结合抗PD-1，并深入探索转录，表观遗传，代谢和功能 与抗PD-1一致的低氧降低相关的结果。我们希望这些研究能够解决 表观遗传学，免疫学和癌症免疫疗法领域的知识差距，发现肿瘤如何 缺氧会使T细胞分化和对抗PD-1的反应偏差，目的是确定新的目标 减轻缺氧驱动T细胞耗尽并克服癌症免疫疗法的障碍。