Epigenetic Regulation of Head and Neck Cancer Immune Evasion

头颈癌免疫逃避的表观遗传调控

• 批准号: 10596193
• 负责人: Chao Lu
• 金额: $ 45.35万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596193
• 关键词: Ablation; Affect; Biochemical; Biological Markers; CRISPR/Cas technology; Cell Line; Chromatin; Clinical; DNA; DNA Modification Methylases; DNMT3a; Development; Disease; EZH2 gene; Elements; Epigenetic Process; Event; FDA approved; Future; Gene Expression Regulation; Genes; Genetic; Genetically Engineered Mouse; Genomic Instability; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Histone H3; Histones; Imaging technology; Immune; Immune Evasion; Immune Targeting; Immune checkpoint inhibitor; Immune system; Immunocompetent; Immunofluorescence Immunologic; Immunologic Surveillance; Immunosuppression; Immunotherapy; Incidence; Individual; Infiltration; Interferons; Knowledge; Leucocytic infiltrate; Link; Mediating; Methylation; Minority; Modeling; Molecular; Mus; Mutation; Nature; Neoplasm Metastasis; Patients; Pattern recognition receptor; Prediction of Response to Therapy; Recurrence; Regulation; Relapse; Reporting; Resistance; Retrotransposon; Role; STAT1 gene; Sampling; Science; Signal Pathway; Survival Rate; Technology; Testing; Therapeutic; Therapeutic Effect; Tissue imaging; Tumor Escape; Tumor Promotion; Tumor-infiltrating immune cells; Work; advanced disease; aggressive therapy; cancer cell; derepression; disorder subtype; epigenetic regulation; epigenetic silencing; epigenome; gain of function; gene repression; genome-wide; histone methyltransferase; humanized mouse; immune cell infiltrate; immunogenicity; in vivo; inhibitor; loss of function; mouse model; multiplexed imaging; mutant; novel; oncohistone; patient response; pharmacologic; predictive marker; recruit; response; single-cell RNA sequencing; therapeutic target; tumor; tumor microenvironment; tumor progression

PROJECT SUMMARY Head and Neck Squamous Cell Carcinomas (HNSCC) affect ~60,000 individuals in the US every year. Despite aggressive treatment, the 5-year survival rate for HNSCC remains ~50% and frequently patients suffer relapse and the development of metastatic lesions. Our previous work showed that NSD1, a histone methyltransferase that specifically catalyzes di-methylation of histone H3 Lys36 (H3K36me2), is frequently inactivated in HNSCC. Deletions, mutations and biochemical inhibition of NSD1 by the oncohistone H3K36M mutation are found in 15% of HNSCC and define a novel disease subgroup with distinct molecular and clinical features. However, the mechanism by which NSD1 inactivation promotes HNSCC development remains unclear. We recently reported that NSD1 inactivation in HNSCC cell lines and patient samples resulted in profound DNA hypomethylation. Our preliminary studies further demonstrated that NSD1 mutations in HNSCC are associated with increased genomic instability and retrotransposon de-repression. Intriguingly, these molecular events are known to promote tumor recognition by host immune system, yet NSD1 mutant tumors are unexpectedly immune “cold” with minimal presence of tumor-infiltrating leukocytes and a reduced interferon response. Therefore, we propose to test the hypothesis that NSD1 inactivation in HNSCC reduces tumor immunogenicity and facilitates immune evasion through epigenetic silencing of the interferon signaling pathway. In Aim 1, we will define the role of NSD1 in HNSCC immune evasion in vivo. We plan to employ syngeneic and genetically engineered mouse models of HNSCC driven by NSD1 loss that have been developed in our lab. Together with the state-of-the-art single-cell RNA-seq and multiplex imaging technologies, we will examine the changes in tumor microenvironment following NSD1 loss. In Aim 2, we will study epigenetic mechanisms by which NSD1 regulates interferon response. We propose to test the model that NSD1 antagonizes H3K27 tri-methylation (H3K27me3), a repressive histone mark catalyzed by EZH2, to maintain STAT1 expression. In Aim 3, using syngeneic and humanized mouse models, we will test if pharmacological inhibition of EZH2 can restore immune infiltration and delay the growth of NSD1- deficient tumors alone or in combination with immune checkpoint inhibitor. Since only a minority of HNSCC patients respond to immune checkpoint inhibitors, our expected results will have immediate translational implication by nominating (1) NSD1/H3K36me2 as biomarkers for predicting therapeutic response to immunotherapy and (2) an FDA-approved EZH2 inhibitor which can be combined with checkpoint inhibitors to target poorly infiltrated, immune “cold” tumors. More broadly, this project will also contribute to our understanding of chromatin-based mechanisms exploited by cancer cells to facilitate immune evasion.

项目摘要 每年在美国，头部和颈部方形细胞癌（HNSCC）影响约60,000人。尽管 积极的治疗，HNSCC的5年生存率仍为约50％，患者经常遭受缓解 以及转移性病变的发展。我们以前的工作表明，NSD1，一种Hisstone甲基转移酶 特异性催化了组蛋白H3 Lys36（H3K36ME2）的二甲基化，在HNSCC中经常失活。 在15％的情况下发现，通过酒精酮H3K36M突变对NSD1的缺失，突变和生化抑制作用。 HNSCC并定义了具有不同分子和临床特征的新型疾病亚组。但是， NSD1失活促进HNSCC发育的机制尚不清楚。我们最近报道 HNSCC细胞系和患者样品中的NSD1失活导致了深度DNA甲基化。我们的 初步研究进一步表明，HNSCC中的NSD1突变与基因组增加有关 不稳定性和逆转座子消除抑制。有趣的是，这些分子事件已知促进肿瘤 宿主免疫系统的识别，但是NSD1突变肿瘤意外地免疫“冷”，最少 肿瘤浸润的白细胞的存在和干扰反应降低。因此，我们建议测试 假设HNSCC中的NSD1灭活可降低肿瘤免疫原性并促进免疫抗性 通过干扰素信号通路的表观遗传沉默。在AIM 1中，我们将定义NSD1在 HNSCC免疫进化在体内。我们计划采用合成和基因工程的鼠标模型 由NSD1损失驱动的HNSCC已在我们的实验室中开发出来。与最先进的单细胞一起 RNA-seq和多重成像技术，我们将检查肿瘤微环境的变化 NSD1损失。在AIM 2中，我们将研究NSD1调节干扰素反应的表观遗传机制。我们 提案测试NSD1拮抗H3K27三甲基化（H3K27ME3）的模型，这是反射性组蛋白标记 由EZH2催化以保持STAT1表达。在AIM 3中，使用合元和人源化的小鼠模型， 我们将测试EZH2的药物抑制是否可以恢复免疫学浸润并延迟NSD1-的生长 单独或与免疫检查点抑制剂结合使用不足。由于只有少数HNSCC 患者应对免疫切除点抑制剂的反应，我们的预期结果将立即翻译 提名（1）NSD1/H3K36ME2作为预测治疗反应的生物标志物的暗示 免疫疗法和（2）FDA批准的EZH2抑制剂，可以与检查点抑制剂结合使用 靶标浸润较差，免疫“冷”肿瘤。从更广泛的角度来看，该项目也将有助于我们的理解 癌细胞探索的基于染色质的机制，以促进免疫进化。