Metabolic impact on T cell-mediated cancer immunity and therapy

代谢对 T 细胞介导的癌症免疫和治疗的影响

基本信息

批准号：
10159227
负责人：
WEIPING ZOU
金额：
$ 64.64万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10159227
关键词：
Address Affect Amino Acids Apoptosis Avidity CD8-Positive T-Lymphocytes Cancer Vaccines Carbon Cell Survival Cell physiology Cells Cellular biology Clinical Clinical Research Colon Carcinoma Data Epigenetic Process Family member Functional disorder Genes Genetic Transcription Glycolysis Goals Histones Human Immune Immune Evasion Immunity Immunotherapeutic agent Immunotherapy Impairment Knowledge Link Malignant Neoplasms Malignant neoplasm of ovary Mediating Metabolic Metabolism Methionine Methionine Metabolism Pathway Methylation Molecular Mus Nature Oncogenic Oxidative Stress PD-1 blockade PD-1/PD-L1 Patients Pattern Phenotype Property Regimen Research Role S-Adenosylmethionine Signal Pathway Signal Transduction Stat5 protein T memory cell T-Lymphocyte Testing Therapeutic Treatment Efficacy Tumor Immunity Vaccination Warburg Effect amino acid metabolism base cancer therapy cancer type cancer vaccination chimeric antigen receptor T cells combinatorial cytotoxic design effector T cell exhaust immune checkpoint blockade neoantigens neoplasm immunotherapy neoplastic cell novel practical application response solute tumor tumor immunology tumor metabolism tumor microenvironment

Address Affect Amino Acids Apoptosis Avidity CD8-Positive T-Lymphocytes Cancer Vaccines Carbon Cell Survival Cell physiology Cells Cellular biology Clinical Clinical Research Colon Carcinoma Data Epigenetic Process Family member Functional disorder Genes Genetic Transcription Glycolysis Goals Histones Human Immune Immune Evasion Immunity Immunotherapeutic agent Immunotherapy Impairment Knowledge Link Malignant Neoplasms Malignant neoplasm of ovary Mediating Metabolic Metabolism Methionine Methionine Metabolism Pathway Methylation Molecular Mus Nature Oncogenic Oxidative Stress PD-1 blockade PD-1/PD-L1 Patients Pattern Phenotype Property Regimen Research Role S-Adenosylmethionine Signal Pathway Signal Transduction Stat5 protein T memory cell T-Lymphocyte Testing Therapeutic Treatment Efficacy Tumor Immunity Vaccination Warburg Effect amino acid metabolism base cancer therapy cancer type cancer vaccination chimeric antigen receptor T cells combinatorial cytotoxic design effector T cell exhaust immune checkpoint blockade neoantigens neoplasm immunotherapy neoplastic cell novel practical application response solute tumor tumor immunology tumor metabolism tumor microenvironment

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项目摘要

Project Summary/Abstract: Effector T cells mediate protective tumor immunity. The goal of tumor immune therapy including check-point blockade and immune vaccination and adoptive effector T cell is to engender long-term protective effector T cell immunity, and cause tumor eradiation in patients with cancer. To this end, effector T cells must traffic into and retain within the tumor microenvironment with potent effector function. Interestingly, the central scientific efforts in the field of tumor immunology are focused on designing different combinatorial therapeutic regimens with PD-L1/PD-1 blockade, exploring new types of CAR-T cells, and evaluating a variety of potential neoantigen cancer vaccination. However, T cells are highly dysfunctional and susceptible to apoptosis in the tumor microenvironment. Our current knowledge of tumor associated effector T cell survival and functionality, and its underlying molecular mechanisms remain poorly understood in patients with cancer. This inadvertent deficiency significantly tempers our efforts toward understanding basic human effector T cell biology, establishing and evaluating immune therapeutic regimens and tumor vaccines in treating patients with cancer. It is essential to conduct comprehensive molecular and functional research on the nature of effector T cell survival and function in the human tumor microenvironment. Abnormal epigenetic pattern correlates to effector T cell malfunction in tumor. However, their potential causal and mechanistic connection is poorly defined. S-adenosylmethionine (SAM) links one-carbon metabolism to methylation status. Using patients with colon cancer and mice bearing different types of cancer, our preliminary studies demonstrated that tumor cells altered methionine metabolism in CD8+ T cells, resulting in insufficient intracellular methionine, low methyl donor SAM, and diminished H3K79me2. Loss of H3K79me2 led to reduced STAT5 expression and activation, resulting in impaired T cell-mediated tumor immunity. Mechanistically, tumor cells were addicted to methionine and outcompeted T cells for methionine via high expression of SLC43A2, a methionine transporter. These data revealed previously unknown mechanisms of association between specific amino acid metabolism, epigenetic alteration and T cell immunity in the tumor microenvironment and identified cancer methionine transporter(s) as a potential novel immunotherapeutic target. Based on this surprising and novel finding, we hypothesize that dysfunctional methionine metabolism is not only a novel immune evasion mechanism, but also a key link between specific histone pattern alteration and survival/functional gene circuits in effector T cells in the tumor microenvironment. We propose two specific aims to mechanistically, functionally, and clinically test our central hypothesis that (1) methionine metabolic circuit controls effector T cell survival and functional potency in the tumor microenvironment, and (2) particular tumor solute carrier family (SLC) member(s) affects T cell methionine metabolism, function and protective immunity.

项目摘要/摘要：效应T细胞介导保护性肿瘤免疫。肿瘤免疫的目标治疗包括检查点封锁和免疫疫苗接种和收养效应t细胞是造成的长期保护效应T细胞免疫，并导致癌症患者消除肿瘤。为此，效应T细胞必须通过有效的效应功能进入并保留在肿瘤微环境中。有趣的是，肿瘤免疫学领域的中心科学努力集中在设计不同与PD-L1/PD-1阻断的组合治疗方案，探索新型CAR-T细胞，并评估各种潜在的新抗原癌症疫苗。然而，T细胞高度功能失调，并且在肿瘤微环境中易受凋亡。我们目前对肿瘤相关效应的知识细胞的存活和功能及其基本分子机制在患者中仍然很少了解癌症。这种无意的缺陷大大降低了我们为理解基本人类的努力效应T细胞生物学，建立和评估免疫治疗方案和肿瘤疫苗治疗癌症患者。对性质进行全面的分子和功能研究至关重要人类肿瘤微环境中效应T细胞的存活和功能。异常表观遗传模式与肿瘤中的效应T细胞故障相关。但是，他们的潜在因果机械连接的定义很差。 S-腺苷甲氨酸（SAM）将一碳代谢联系起来甲基化状态。使用结肠癌患者和患有不同类型癌症的小鼠，我们的初步研究表明，肿瘤细胞改变了CD8+ T细胞中蛋氨酸的代谢，导致不足细胞内蛋氨酸，低甲基供体SAM和H3K79me2降低。 H3K79me2的损失导致减少 STAT5表达和激活，导致T细胞介导的肿瘤免疫受损。机械上，肿瘤通过高表达SLC43A2，A蛋氨酸上瘾的细胞和甲基氨酸的蛋氨酸，A 蛋氨酸转运蛋白。这些数据揭示了先前未知的特定之间关联机制肿瘤微环境中的氨基酸代谢，表观遗传学改变和T细胞免疫癌蛋氨酸转运蛋白是一种潜在的新型免疫治疗靶标。基于这个令人惊讶和新颖的发现，我们假设功能失调的蛋氨酸代谢不是只有一种新型的免疫逃避机制，也是特定组蛋白模式改变与肿瘤微环境中效应T细胞中的生存/功能基因回路。我们提出了两个特定的旨在在机械，功能和临床上检验我们的中心假设，即（1）蛋氨酸代谢电路控制肿瘤微环境中的效应T细胞存活和功能效力，并且（2）特定肿瘤溶质载体家族（SLC）成员影响T细胞蛋氨酸代谢，功能和保护性免疫。