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.

项目总结 在美国，头颈部鳞状细胞癌(HNSCC)每年影响约60,000人。尽管 积极的治疗，HNSCC的5年存活率保持在50%左右，患者经常复发 以及转移灶的发展。我们之前的工作表明，组蛋白甲基转移酶NSD1 组蛋白H3Lys36(H3K36me2)特异性催化组蛋白H3Lys36的二甲基化，在HNSCC中经常失活。 癌基因H3K36M突变导致NSD1基因缺失、突变和生化抑制的发生率为15% 并定义了具有不同分子和临床特征的新的疾病亚群。然而， NSD1失活促进HNSCC发生的机制尚不清楚。我们最近报道了 在HNSCC细胞系和患者样本中，NSD1的失活导致了严重的DNA低甲基化。我们的 初步研究进一步证明，HNSCC中的NSD1突变与基因组增加有关 不稳定和反转录转座子抑制。有趣的是，这些分子事件已知会促进肿瘤 被宿主免疫系统识别，但NSD1突变的肿瘤出人意料地免疫力极低 肿瘤浸润性白细胞的存在和干扰素反应的降低。因此，我们建议测试 假设HNSCC中NSD1失活降低了肿瘤的免疫原性并促进了免疫逃避 通过对干扰素信号通路的表观遗传沉默。在目标1中，我们将定义NSD1在 HNSCC在体内的免疫逃避。我们计划使用同基因和基因工程的小鼠模型 由我们实验室开发的NSD1丢失驱动的HNSCC。与最先进的单细胞 Rna-seq和多重成像技术，我们将观察肿瘤微环境的变化。 NSD1损失。在目标2中，我们将研究NSD1调节干扰素反应的表观遗传学机制。我们 建议测试NSD1拮抗抑制性组蛋白标志物H3K27三甲基化(H3K27me3)的模型 在EZH2的催化下，维持STAT1的表达。在目标3中，使用同基因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渗透，延缓NSD1- 缺陷性肿瘤单独或与免疫检查点抑制剂联合使用。因为只有一小部分HNSCC 患者对免疫检查点抑制剂有反应，我们的预期结果将立即转化为 提名(1)NSD1/H3K36me2作为预测治疗反应的生物标志物的意义 免疫疗法；(2)FDA批准的EZH2抑制剂，可与检查点抑制剂联合使用 靶向浸润性差、免疫能力差的“冷”肿瘤。更广泛地说，这个项目也将有助于我们理解 基于染色质的机制被癌细胞用来促进免疫逃避。