Investigating altered T-cell metabolism during chronic antigen encounter

项目摘要/摘要 尽管最近在针对跨恶性肿瘤的免疫检查点方面取得了进展，但许多患者未能 对治疗有反应，提出了免疫抑制的替代机制。体内代谢功能障碍 肿瘤浸润性T细胞已成为长期抗肿瘤免疫的一种潜在机制 受伤了。然而，代谢改变抑制肿瘤内T细胞功能的机制， 仍有待充分研究。细胞代谢物不仅提供增殖所需的生物能量 不仅可以调节免疫细胞，还可以作为染色质修饰的底物来调节基因表达。 该提案中提供的初步数据利用体外和体内系统相结合的方式来探索 肿瘤抗原慢性暴露过程中T细胞的代谢倾向。在这些条件下，T细胞 经历高水平的氧化应激。这损害了T细胞氧化葡萄糖和 谷氨酰胺在TCA循环中，导致生物能量妥协，损害核苷酸生物合成和 改变DNA和组蛋白去甲基化反应的底物的可用性。增强氧化还原能力 体内动态平衡对体内和体外抗肿瘤T细胞免疫均有一定的促进作用。因此，它的功效 肿瘤微环境中T细胞的数量可能主要受到代谢变化的限制 氧化还原压力。这一假设将通过(1)使用体外和体内模型相结合的方式进行严格检验 在小鼠和原发患者肿瘤中T细胞耗竭的研究以确定慢性抗原驱动的影响 T细胞增殖、染色质修饰和效应器功能的代谢变化，(2)决定如何 半胱氨酸限制加剧了肿瘤微环境中的T细胞功能障碍，以及(3)确定 无论是通过增加细胞内半胱氨酸的可获得性还是通过限制细胞内的氧化还原动态平衡 氧化应激的产生可以逆转代谢T细胞功能障碍，增强抗肿瘤免疫。这个 拟议中的研究将扩大增强癌症免疫反应的策略， 尤其是对抗PD-1治疗无效的患者。申请人桑托莎·瓦德哈纳博士， 纪念斯隆·凯特琳癌症中心淋巴瘤服务的一名助理概述了 基于他在免疫学和细胞新陈代谢方面的科学背景以及 他在内科肿瘤学和免疫疗法方面的临床训练。Vardhana博士将进行拟议中的研究 在克雷格·汤普森博士的指导下，国际公认的免疫学和 新陈代谢与培养成功的内科科学家的良好记录，与博士的共同指导。 Jedd Wolchok，一位高度认可的癌症免疫治疗专家，在审讯T- 在小鼠模型和原始患者样本中的细胞功能。MSKCC提供了理想的机构 为Vardhana博士开始拟议的研究计划并过渡到一个职位的环境 独立的学术研究人员，拥有自己的实验室和R01资金。

PROJECT SUMMARY/ABSTRACT Despite recent advances in the targeting of immune checkpoints across malignancies, many patients fail to respond to treatment, suggesting alternative mechanisms of immunosuppression. Metabolic dysfunction within tumor-infiltrating T-cells has emerged as a potential mechanism by which long-term anti-tumor immunity is impaired. The mechanism by which altered metabolism suppresses intratumoral T-cell function, however, remains to be fully characterized. Cellular metabolites not only supply the bioenergetics needs of proliferating immune cells, but also regulate gene expression by serving as the substrates for chromatin modifications. Preliminary data presented in this proposal utilize a combination of in vitro and in vivo systems to explore the metabolic liabilities of T-cells during chronic exposure to tumor antigens. Under these conditions, T-cells experience high levels of oxidative stress. This compromises the ability of T-cells to oxidize glucose and glutamine within the TCA cycle, leading to bioenergetic compromise that impairs nucleotide biosynthesis and alters the availability of substrates for DNA and histone demethylation reactions. Enhancing redox homeostasis has beneficial effects on anti-tumor T-cell immunity in vitro as well as in vivo. Thus, the efficacy of T-cells within the tumor microenvironment may be primarily limited by metabolic alterations that generate redox stress. This hypothesis will be rigorously tested by (1) using a combination of in vitro and in vivo models of T-cell exhaustion in both mice and primary patient tumors to define the impact of chronic antigen-driven metabolic alterations on T-cell proliferation, chromatin modifications, and effector function, (2) determining how cysteine limitation exacerbates T-cell dysfunction within the tumor microenvironment, and (3) determining whether enhancing redox homeostasis, either by increasing intracellular cysteine availability or limiting the generation of oxidative stress can reverse metabolic T-cell dysfunction and enhance anti-tumor immunity. The proposed investigations will expand the armamentarium of strategies to enhance immune responses in cancer, particularly for the patients who are unresponsive to anti-PD-1 therapy. The applicant, Dr. Santosha Vardhana, an Assistant Attending with the Lymphoma Service at Memorial Sloan Kettering Cancer Center, has outlined a 5-year career plan that builds on his scientific background in immunology and cellular metabolism as well as his clinical training in medical oncology and immunotherapy. Dr. Vardhana will conduct the proposed research under the mentorship of Dr. Craig Thompson, an internationally recognized expert in immunology and metabolism with a strong track record of training successful physician scientists, with co-mentorship by Dr. Jedd Wolchok, a highly recognized expert in cancer immunotherapy with significant experience interrogating T- cell function in both mouse models and primary patient samples. MSKCC provides the ideal institutional environment for Dr. Vardhana to embark on the proposed research program and transition to a position as an independent academic investigator with his own laboratory and R01 funding.