Tumor-infiltrating T cell metabolic dysfunction and genetic reprogramming for effective immunotherapy

肿瘤浸润 T 细胞代谢功能障碍和基因重编程以实现有效的免疫治疗

• 批准号: 9435313
• 负责人: Nicole E Scharping
• 金额: $ 4.55万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-14 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9435313
• 关键词: Acetyltransferase; Address; Affect; Award; Biogenesis; Biological Assay; Biological Process; Buffers; CD8-Positive T-Lymphocytes; CD8B1 gene; Calcium; Cancer Cell Growth; Cells; Cellular Metabolic Process; Cellular biology; Characteristics; Chromatin; Chronic; Environment; Epigenetic Process; Functional disorder; Genetic; Genetic Models; Glucose; Goals; Human; Hypoxia; Immune; Immune Cell Suppression; Immune system; Immunosuppressive Agents; Immunotherapy; In Vitro; Knowledge; Ligands; Malignant Neoplasms; Metabolic; Metabolic Pathway; Metabolism; Metformin; Mitochondria; Mus; Mutate; Nature; Nutrient; Organelles; Oxygen; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Postdoctoral Fellow; Recruitment Activity; Repression; Research; Research Project Grants; Synapses; T cell differentiation; T memory cell; T-Cell Activation; T-Lymphocyte; Therapeutic; Therapeutic Uses; Tumor Burden; Tumor Immunity; Tumor Suppression; Tumor-Infiltrating Lymphocytes; Work; cancer cell; cancer immunotherapy; cancer therapy; chimeric antigen receptor; cytokine; design; exhaust; exhaustion; experience; genetic profiling; immune checkpoint blockade; improved; killings; melanoma; neoplastic cell; overexpression; pre-doctoral; prevent; rapid growth; receptor; release of sequestered calcium ion into cytoplasm; response; success; therapy outcome; tool; transcription factor; tumor; tumor microenvironment

Abstract Tumor-infiltrating T cell metabolic dysfunction and genetic reprogramming for effective immunotherapy The ability to target and destroy mutated cells is an essential characteristic of the immune system. Despite this attribute, the immune system largely fails to eliminate cancer once a tumor is established. This is due in part to the immunosuppressive nature of the tumor microenvironment (TME), which inhibits CD8+ tumor infiltrating T lymphocytes (CD8+ TIL) from becoming activated and killing their target cells. While it is known that the TME can directly inhibit CD8+ TIL through receptor-ligand interactions and suppressive cytokines to cause phenotypically and functionally exhausted T cells, it is increasingly understood that the TME is also metabolically suppressive. Tumor cells utilize an abundance of metabolites due to their proliferative nature, creating an additional suppressive mechanism for CD8+ TIL, as they need adequate nutrients for effector functions and to fuel their own proliferative nature. In this NCI Predoctoral to Postdoctoral Fellow Transition Award (F99/K00) application, the metabolic deficiencies of CD8+ TIL are described, showing CD8+ TIL experience significant loss of mitochondrial mass and function. This is due to repression of mitochondrial biogenesis transcription factor PGC1α, due to chronic Akt activation in TIL. When PGC1α was overexpressed in CD8+ TIL, it not only led to increased mitochondria, but improved TIL effector function and decreased tumor burden. These results led to the proposed studies: to further understand why mitochondria are important to TIL function. It is hypothesized that mitochondria are the defining organelle between a functional memory T cell and a dysfunctional exhausted T cell. To explore this hypothesis, T cells will be rendered metabolically- deficient in vitro through pharmacologic depletion of mitochondrial function. These metabolically deficient T cells (called Rho0 T cells) will be used to explore how mitochondria may be essential for calcium buffering to limit NFAT and an exhaustion genetic profile, as well as how mitochondria may be required for preventing an exhaustion epigenetic profile. After the completion of these studies, the applicant will transition to postdoctoral studies, where they will further explore TIL dysfunction, but with the goal of a translational, therapeutic outcome. The applicant will study how chimeric antigen receptor (CAR) T cells may be improved upon and used therapeutically in human T cells. Understanding how T cells become dysfunctional in cancer is important for both our understanding of T cell biology, and for improving targeted cancer immunotherapy.

抽象的 肿瘤浸润的T细胞代谢功能障碍和遗传重编程有效免疫疗法 靶向和破坏突变细胞的能力是免疫系统的重要特征。尽管如此 属性，一旦建立肿瘤，免疫系统就会在很大程度上消除癌症。这部分是由于 肿瘤微环境（TME）的免疫抑制性质，抑制CD8+肿瘤浸润T 淋巴细胞（CD8+ TIL）被激活并杀死其靶细胞。虽然知道TME 可以直接通过受体配体相互作用和抑制细胞因子抑制CD8+ TIL引起 表型和功能耗尽的T细胞，越来越了解TME也是 代谢抑制。肿瘤细胞由于其增殖性质而利用代谢物的抽象 为CD8+ TIL创建额外的抑制机制，因为它们需要足够的效应营养物质 功能并助长自己的扩散性质。在这个NCI占主导地位到博士后同伴过渡 描述了CD8+ TIL的代谢缺陷奖奖（F99/K00），显示了CD8+ TIL 线粒体质量和功能的显着丧失。这是由于线粒体的表达 生物发生转录因子PGC1α，由于TIL中的慢性AKT激活。当PGC1α过表达时 在CD8+ TIL中，它不仅导致线粒体增加，而且提高了TIL效应子功能并减少肿瘤 负担。这些结果导致了拟议的研究：进一步理解为什么线粒体对于直截了当很重要 功能。假设线粒体是功能记忆T细胞之间的定义细胞器 和功能障碍的T细胞功能失调。为了探索这一假设，T细胞将被代谢呈现 通过线粒体功能的药理学耗竭在体外防御性。这些代谢缺陷的T 细胞（称为Rho0 T细胞）将用于探索线粒体如何对于钙缓冲至 限制NFAT和精疲力尽的遗传特征，以及如何防止线粒体 精疲力尽的表观遗传学轮廓。完成这些研究后，申请人将过渡到博士后 研究，他们将进一步探索直到功能障碍，但以翻译的治疗目的 结果。申请人将研究如何改善嵌合抗原受体（CAR）T细胞，并 在人类T细胞中使用治疗。了解T细胞如何在癌症中功能失调很重要 为了了解我们对T细胞生物学的理解，以及改善靶向癌症的免疫疗法。