Epigenetic Regulation of Head and Neck Cancer Immune Evasion

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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.