Metabolic impact on T cell-mediated cancer immunity and therapy

项目摘要/摘要：效应器T细胞介导保护性肿瘤免疫。肿瘤免疫的目标 包括检查点封锁和免疫接种在内的治疗将产生过继效应性T细胞 长期保护效应者T细胞免疫，并引起肿瘤患者的肿瘤放射。为此， 效应性T细胞必须进入并保留在具有强大效应功能的肿瘤微环境中。 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的 PD-L1/PD-1阻断的联合治疗方案，探索新型CAR-T细胞，以及 评估各种潜在的新抗原癌症疫苗接种。然而，T细胞高度功能失调， 在肿瘤微环境中易发生细胞凋亡。我们目前对肿瘤相关效应器T的认识 患者对细胞存活和功能及其潜在的分子机制仍知之甚少 得了癌症。这种无意中的缺陷极大地影响了我们理解基本人类的努力。 效应T细胞生物学、免疫治疗方案和肿瘤疫苗的建立与评价 癌症患者。对自然界进行全面的分子和功能研究是必要的。 效应T细胞在人类肿瘤微环境中的存活和功能。 表观遗传模式异常与肿瘤效应T细胞功能障碍有关。然而，它们的潜在因果关系 机械性的联系也没有明确的定义。S-腺苷蛋氨酸将一碳代谢与 甲基化状态。利用结肠癌患者和携带不同类型癌症的小鼠，我们的初步研究 研究表明，肿瘤细胞改变了CD8T细胞中的蛋氨酸代谢，导致甲硫氨酸不足 胞内蛋氨酸、低甲基供体SAM和抑制H3K79me2。H3K79me2的损失导致减少 Stat5的表达和激活，导致T细胞介导的肿瘤免疫功能受损。从力学上讲，肿瘤 细胞对蛋氨酸上瘾，并通过高表达SLC43A2，a 蛋氨酸转运蛋白。这些数据揭示了以前未知的特定基因之间的关联机制 肿瘤微环境中的氨基酸代谢、表观遗传学改变与T细胞免疫 肿瘤蛋氨酸转运蛋白(S)作为潜在的免疫治疗新靶点。 基于这一令人惊讶和新奇的发现，我们假设功能失调的蛋氨酸代谢不是 不仅是一种新的免疫逃避机制，而且是特异组蛋白模式改变与 肿瘤微环境中效应T细胞的存活/功能基因回路。我们提出了两个具体的 目的是从机械、功能和临床上检验我们的中心假设：(1)蛋氨酸代谢 电路控制效应T细胞在肿瘤微环境中的存活和功能潜能，以及(2)特定 肿瘤溶质载体家族成员S对T细胞蛋氨酸代谢、功能及保护的影响 豁免权。

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.