Abstract 5743: Aberrant microRNA expression dysregulates the head and neck squamous cell carcinoma immune landscape

Abstract

Abstract Immunotherapy has emerged as one of the most promising treatments for several cancers, including head and neck squamous cell carcinoma (HNSCC). However, the failure of a large percentage of patients to respond to immunotherapy remains the ultimate obstacle to successful treatment. Etiology-associated dysregulation of genes involved in the immune system may be central to the development of differential clinical response to immunotherapy. Smoking, one of the main causes of HNSCC, may have a dual effect on the efficacy of immunotherapy. On one hand, mutations caused by tobacco are very effective in promoting antigenicity, thus enhancing immunogenicity. On the other hand, tobacco may alter cellular processes in a way that causes immunotherapy to fail. For example, microRNA-induced mRNA degradation or inhibition of translation could be critical in the dysregulation of immune associated (IA) genes. Using next generation sequencing data from The Cancer Genome Atlas (TCGA), we identified a comprehensive panel of dysregulated IA genes, including tobacco-associated dysregulated IA genes, in HNSCC samples compared to normal controls. To validate our findings, normal and cancer epithelial cell lines (HaCaT and UMSCC22B) were exposed to physiologically relevant doses of cigarette smoke condensate, and qPCR was performed to determine tobacco regulation of IA gene expression. Several IA genes, including FOXA2, SEMA3G, PLAU, OLR1, and DKK1, were significantly dysregulated and corroborated with the direction of dysregulation from our analysis of clinical data. The expressions of these genes also showed significant correlation with patient survival in Kaplan-Meier survival analysis (univariate cox regression, p<0.05). Several of these genes correlate significantly with clinical variables, including neoplasm histological grade and pathological stage, as assessed using the Kruskal-Wallis test (p<0.05). In order to understand the molecular mechanism by which these IA genes are dysregulated, we also identified a panel of tobacco-dysregulated microRNAs in HNSCC and distinguished those that can potentially target dysregulated IA genes using the online target prediction service provided by TargetScan, which utilizes a computational model that takes into account miRNA-mRNA complementarity as well as conservation of binding sites. We found a large number of microRNAs to be negatively enriched in relation to IA gene expression using gene set enrichment analysis (GSEA). These findings will be very important in understanding not only how tobacco use is critical to the pathogenesis and progression of HNSCC, but also the molecular mechanisms underlying the failure of immunotherapy for certain patients. Furthermore, these IA genes and their regulatory microRNAs in HNSCC can potentially be therapeutically targeted as a novel treatment strategy or as a complement to existing immunotherapy treatments. Citation Format: Yuanhao Qu, Wei Tse Li, Christine O. Honda, Omar Saad, Aswini R. Krishnan, Sunil J. Advani, Weg M. Ongkeko. Aberrant microRNA expression dysregulates the head and neck squamous cell carcinoma immune landscape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5743.