Epigenetic mechanisms regulate cancer development and tumor immune responses

项目总结 表观遗传机制调节染色质结构和基因表达以指导生物 发育和组织动态平衡，它的破坏在癌症中普遍存在。表观遗传破坏可能导致 几乎一半的人类癌症都带有表观遗传学的突变 监管者。表观遗传机制也越来越被认为是肿瘤的主要调节因素。 免疫反应促使人们有兴趣寻找利用这一点造福癌症患者的方法。组蛋白 修饰基因KMT2C(ML3)和KMT2D(MLL4)是所有癌症中最常见的突变基因之一 头颈部鳞状细胞癌(HNSCC)的突变率特别高。值得注意的是， 尽管KMT2C/D突变和HNSCC的流行，KMT2C/D如何在上皮细胞中发挥作用 动态平衡和致癌机制尚不清楚。我的初步数据显示KMT2C/D- H3K4me1轴在小鼠体内口腔上皮细胞中的表达导致口腔上皮细胞的增生。考虑到固有的 表观遗传改变的可逆性，这些改变可能是靶向的抑制剂来预防或治疗 HNSCC。我早期的论文工作支持这一点，并提出KMT2C/D-H3K4me1轴的功能障碍可能 通过抑制相反的H3K4me1/2组蛋白去甲基酶LSD1来纠正。我假设损失的是 KMT2C/D在体内破坏口腔上皮细胞的动态平衡，促进口腔鳞癌的发生 LSD1抑制剂可以逆转这种改变。我将按照提议在F99阶段的团契中测试这一点。 具体来说，我将研究口腔上皮中Kmt2d或Kmt2c缺失的小鼠 用组织病理学、RNA序列和芯片序列进行动态平衡。我也会测试Kmt2c/d的丢失是否会促进 活体上皮癌变，采用公认的口腔癌变模型(4NQO)，如果 使用LSD1抑制剂可以逆转这些改变。这些研究的目标是确定Kmt2c/d是否起作用 作为鳞状细胞癌的肿瘤抑制因子，并确定针对HNSCC患者的潜在的新的表观基因组靶向治疗。 尽管免疫疗法取得了显著的成功，但许多患者对此没有反应或变得 对这些治疗有抵抗力。许多研究已经证实，表观遗传靶向药物可能会增强 免疫疗法。然而，表观遗传机制如何在肿瘤发生或发展过程中调节肿瘤免疫 免疫疗法还没有完全被理解。为此，在AIM中提议的这一研究金的K00阶段 2、我将以我在细胞和肿瘤表观遗传学方面的技术技能和科学知识为基础， 肿瘤免疫学和免疫表观遗传学博士后培训。具体地说，我将确定如何 肿瘤和免疫细胞群的表观遗传变化调节肿瘤免疫能力，免疫细胞 TME中的种群和免疫细胞功能。最终，这些发现将确定表观遗传学 可以利用机制来改善免疫治疗的结果。

PROJECT SUMMARY Epigenetic mechanisms regulate chromatin structure and gene expression to direct organismal development and tissue homeostasis, disruption of which is pervasive in cancer. Epigenetic disruption can lead to the acquisition of each hallmark of cancer and almost half of all human cancers bear mutations in epigenetic regulators. Epigenetic mechanisms are also being increasingly appreciated as a major regulator of the tumor immune response prompting interest in finding ways to leverage this to benefit cancer patients. The histone modifiers KMT2C (MLL3) and KMT2D (MLL4) are amongst the most frequently mutated genes in all of cancer with particularly high rates of mutations in head and neck squamous cell carcinoma (HNSCC). Remarkably, despite the prevalence of KMT2C/D mutations and HNSCC, how KMT2C/D function during epithelial homeostasis and carcinogenesis remains unknown. My preliminary data suggest dysfunction of the KMT2C/D- H3K4me1 axis in the oral epithelium of mice in vivo results in oral epithelial hyperplasia. Given the inherent reversibility of epigenetic changes, these alterations may be targetable with inhibitors to prevent or treat HNSCC. My early thesis work supports this and suggests that dysfunction of the KMT2C/D-H3K4me1 axis may be corrected by inhibiting the opposing H3K4me1/2 histone demethylase LSD1. I hypothesize that loss of KMT2C/D disrupts oral epithelial homeostasis in vivo, promotes oral SCC carcinogenesis, and that these alterations may be reversed with LSD1 inhibitors. I will test this in the F99 phase of this fellowship as proposed in Aim 1. Specifically, I will study mice with deletions of Kmt2d or Kmt2c in the oral epithelium during homeostasis using histopathology, RNA-seq, and ChIP-seq. I will also test if loss of Kmt2c/d promotes epithelial carcinogenesis in vivo, employing a well-established model of oral carcinogenesis (4NQO), and if these alterations may be reversed using Lsd1 inhibitors. The goal of these studies is to identify if Kmt2c/d act as tumor suppressors in SCC and identify potential novel, epigenome targeting therapies for HNSCC patients. Despite the remarkable successes of immunotherapies, many patients do not respond to or become resistant to these treatments. Numerous studies have identified that epigenetic-targeting drugs may potentiate immunotherapies. However, how epigenetic mechanisms regulate tumor immunity during tumorigenesis or immunotherapy is incompletely understood. To this end, in the K00 phase of this fellowship as proposed in Aim 2, I will build upon my technical skills and scientific knowledge in cellular and tumor epigenetics by pursuing post-doctoral training in tumor immunology and immunoepigenetics. Specifically, I will determine how epigenetic alterations in tumor and immune cell populations regulate tumor immune competency, immune cell populations in the TME, and immune cell functions. Ultimately, these findings will identify how epigenetic mechanisms may be leveraged to improve outcomes of immunotherapy treatments.