Epigenetic mechanisms regulate cancer development and tumor immune responses

项目摘要 表观遗传机制调节染色质结构和基因表达，以指导生物体 发育和组织稳态，其破坏在癌症中普遍存在。表观遗传破坏会导致 几乎一半的人类癌症携带表观遗传突变， 监管部门表观遗传机制作为肿瘤的主要调节因子也越来越受到重视 免疫反应促使人们对寻找利用这一点使癌症患者受益的方法产生兴趣。组蛋白 修饰物KMT 2C（MLL 3）和KMT 2D（MLL 4）是所有癌症中最常见的突变基因之一， 在头颈部鳞状细胞癌（HNSCC）中突变率特别高。值得注意的是， 尽管KMT 2C/D突变和HNSCC的流行，但KMT 2C/D在上皮细胞中的功能如何？ 体内平衡和致癌作用仍然未知。我的初步数据显示KMT 2C/D功能障碍- H3 K4 me 1轴在小鼠口腔上皮中的表达导致口腔上皮增生。鉴于固有的 表观遗传变化的可逆性，这些改变可以用抑制剂靶向，以预防或治疗 HNSCC。我早期的论文工作支持这一点，并表明KMT 2C/D-H3 K4 me 1轴功能障碍可能与KMT 2C/D-H3 K4 me 1轴功能障碍有关。 通过抑制相反的H3 K4 me 1/2组蛋白脱甲基酶LSD 1来纠正。我推测， KMT 2C/D在体内破坏口腔上皮的稳态，促进口腔SCC的癌变，并且这些 改变可以用LSD 1抑制剂逆转。我将在F99阶段的奖学金计划中对此进行测试 目标1。具体地说，我将研究口腔上皮中Kmt 2d或Kmt 2c缺失的小鼠， 使用组织病理学、RNA-seq和ChIP-seq的稳态。我还将测试Kmt 2c/d的丢失是否会促进 上皮癌发生在体内，采用一个良好的口腔癌发生模型（4 NQO），如果 这些改变可以用Lsd 1抑制剂逆转。这些研究的目的是确定Kmt 2c/d是否起作用， 作为SCC中的肿瘤抑制剂，并确定HNSCC患者的潜在新型表观基因组靶向疗法。 尽管免疫疗法取得了显着的成功，但许多患者对免疫疗法没有反应或变得不敏感。 对这些治疗有抵抗力。许多研究已经确定，表观遗传靶向药物可以增强 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， 免疫疗法还不完全了解。为此，在Aim建议的K 00阶段， 2.我将通过追求细胞和肿瘤表观遗传学方面的技术技能和科学知识， 肿瘤免疫学和免疫表观遗传学博士后培训。具体来说，我将决定如何 肿瘤和免疫细胞群体中的表观遗传改变调节肿瘤免疫能力、免疫细胞 TME中的群体和免疫细胞功能。最终，这些发现将确定表观遗传如何 可以利用这些机制来改善免疫疗法治疗的结果。

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.