Decoding tobacco-related oral cancer ecosystem by integrative approach

项目概要 已知的口腔癌危险因素包括吸烟和饮酒以及人乳头瘤病毒 (HPV) 感染。 烟草使用和 HPV 感染之间存在明显的相互作用。吸烟者的比例明显更高 持续口腔 HPV 感染是发生口腔癌的重要危险因素。吸烟患者—— 相关口腔癌预后较差。烟草除了对基因组 DNA 造成明显的损害外， 接触香烟烟雾也会显着影响免疫系统。近年来免疫疗法已成为 口腔癌的一种有前途的治疗选择。程序性细胞死亡-1（PD-1）是临床上最常见的死亡细胞之一。 重要的检查点分子已被证明在与其配体结合后抑制 T 细胞功能， PD-L1 和 PD-L2。 Nivolumab 和 pembrolizumab 是两种最有效和安全的 PD-1 抑制剂 口腔癌管理的数据。虽然持续使用烟草的有害影响已被 多年来建立的，烟草使用对肿瘤免疫微环境（TIME）的影响和 口腔癌免疫治疗疗效的研究很少。在本提案中，我们将全面 通过综合多组学方法评估烟草相关对口腔癌生态系统的影响， 利用口腔癌特异性 TIME 识别新型治疗药物，并开发口腔癌特异性药物 推进烟草相关癌症研究领域的门户网站。

PROJECT SUMMARY Known risk factors for oral cancers are tobacco and alcohol use and human papillomavirus (HPV) infection. There is a clear interaction between tobacco use and HPV infection. Smokers have a significantly higher rate of persistent oral HPV infection which is a significant risk factor to develop oral cancer. Patients with tobacco- related oral cancers have poor prognosis. Apart from the obvious damage tobacco causes to genomic DNA, cigarette smoke exposure also significantly impacts the immune system. Recently immunotherapy has become a promising therapeutic option in oral cancer. Programmed cell death-1 (PD-1) is one of the clinically significant checkpoint molecules that have been shown to suppress T-cell function upon binding to its ligands, PD-L1 and PD-L2. Nivolumab and pembrolizumab are the two PD-1 inhibitors with the most efficacy and safety data in management of oral cancer. While the detrimental effects of continued tobacco use have been established over the years, the effects of tobacco use in the tumor immune microenvironment (TIME) and immunotherapy efficacy in oral cancers are poorly investigated. In this proposal, we will comprehensively evaluate the tobacco-related effects on the oral cancer ecosystem through integrated multi-omics approaches, identify novel therapeutic agents leveraging the oral cancer-specific TIME, and develop an oral cancer specific web portal to advance the field in tobacco-related cancer research.