Epigenetic regulation of metabolic stress pathways in melanoma infiltrating lymphocytes- Resubmission

黑色素瘤浸润淋巴细胞代谢应激途径的表观遗传调控 通过检查点抑制和过继细胞疗法释放抗肿瘤淋巴细胞是令人难以置信的 对抗转移性黑色素瘤的有效策略。T细胞过继疗法在以下患者中显示出成功， 检查点抑制剂治疗失败。肿瘤浸润淋巴细胞（TIL）在过继治疗中面临着一个新的挑战。 当它们遇到肿瘤微环境时，包括缺氧条件，葡萄糖限制， 和免疫抑制-所有这些细胞必须克服以发挥治疗作用。虽然 已知表观遗传机制在淋巴细胞活化中起重要作用，这些细胞的机制 可能用于适应实体瘤环境的极端条件还没有得到很好的理解。的 过继性T细胞治疗黑色素瘤的完全肿瘤消退率为10-20%;因此， 过继细胞疗法需要对抗表观遗传免疫调节以达到其全部潜力。的 甲基转移酶EZH 2（Zeste同源物2的增强子）是一种组蛋白修饰酶，已显示其 在淋巴细胞活化过程中被快速诱导，并且是黑色素瘤中葡萄糖剥夺的靶点 微环境这项工作的中心假设是组蛋白甲基转移酶EZH 2保护TILs 代谢应激诱导的细胞凋亡以下目标将用于检验这一假设：目标1：定义 EZH 2抑制期间淋巴细胞组蛋白表观遗传景观的变化。目标2：定义 H3 K27 me 3缺失使淋巴细胞对代谢应激敏感的机制。目标3：展示 肿瘤特异性淋巴细胞中EZH 2过表达的治疗潜力。在这项研究的最后，我觉得 强烈地认为，一种新的机制将被定义为在代谢应激过程中保护淋巴细胞。 此外，我打算设计一种新的方法来保护淋巴细胞免受代谢性免疫抑制。 我组建了一个由表观遗传学、癌症免疫学和蛋白质组学领导人组成的指导团队， 促进这种独特和严格的培训，准备我追求作为一个独立的学术生涯 科学家

Epigenetic regulation of metabolic stress pathways in melanoma infiltrating lymphocytes Unleashing antitumor lymphocytes through checkpoint inhibition and adoptive cell therapies are incredibly promising strategies to fight metastatic melanoma. T cell adoptive therapies have shown success in patients that have failed checkpoint inhibitor therapies. The tumor-infiltrating lymphocytes (TIL) in adoptive therapy face a host of stresses as they encounter the tumor microenvironment including hypoxic conditions, glucose restriction, and immune suppression - all of which these cells must overcome to function therapeutically. Although it is known that epigenetic mechanisms play an important role in lymphocyte activation, the mechanisms these cells might use to adapt to the extreme conditions of the solid tumor environment are not well understood. The complete tumor regression rates for adoptive T cell therapy for melanoma are 10-20%; thus, new approaches to combat epigenetic immunomodulation are needed for adoptive cell therapies to reach their full potential. The methyltransferase EZH2 (Enhancer of Zeste Homolog 2) is a histone-modifying enzyme that has been shown to be rapidly induced during lymphocyte activation and a target of glucose deprivation in the melanoma microenvironment. The central hypothesis of this work is that the histone methyltransferase EZH2 protects TILs from metabolic stress-induced apoptosis. The following aims will be used to test this hypothesis: Aim1: Define changes in the histone epigenetic landscape of lymphocytes during EZH2 inhibition. Aim 2: Define the mechanism(s) by which loss of H3K27me3 sensitizes lymphocytes to metabolic stress. Aim 3: Demonstrate the therapeutic potential of EZH2 over-expression in tumor-specific lymphocytes. At the end of this study, I feel strongly that a novel mechanism will be defined for protection of lymphocytes during metabolic stress. Additionally, I intend to devise a novel approach for protecting lymphocytes from metabolic immunosuppression. I have assembled a mentoring team of leaders in epigenetics, cancer immunology, and proteomics that will facilitate this unique and rigorous training, preparing me to pursue a career as an independent academic scientist.