Improving Treatment Algorithms for Veterans with Oropharyngeal Cancer

口咽癌在退伍军人中的发病率迅速增加， 很大程度上是因为接触了人乳头瘤病毒（HPV）。虽然口咽部的存活率 与人乳头状瘤病毒（HPV+OPSCC）相关的鳞状细胞癌是极好的 在一般人群中，退伍军人的情况仍然令人沮丧，近1/2的患者 在确诊后5年内死于疾病。人们认为， 部分原因是肿瘤对化疗-放疗治疗方案的反应较低。 我们小组和其他人的初步数据表明，这种治疗反应的降低可能是 部分原因是烟草暴露，这在退伍军人中非常普遍， HPV+OPSCC。假设的作用机制是烟草诱导的免疫抑制， 抑制淋巴细胞和其他免疫细胞的正常抗肿瘤活性的环境 在癌症治疗期间。 在目前的建议中，我们将首先描述和量化烟草的相对影响， HPV+OPSCC退伍军人中暴露对生存率的影响（目标1）。这一点至关重要，因为 实施AJCC分级手册第8版，大幅降低OPSCC 基于HPV状态（HPV相关vs非HPV相关），但不考虑 烟草暴露对生存的潜在关键影响。鉴于广泛的，广泛的 烟草暴露，我们和其他人已经证明，在退伍军人与OPSCC，这代表了一个 重要的临床和翻译的第一步，可能提高生存的退伍军人与此 疾病 然后，我们将表征Th 1 T淋巴细胞和髓源性抑制细胞， HPV+OPSCC肿瘤中肿瘤免疫微环境（TIME）的MDSC组分， 烟草暴露的函数（目标2）。这将使我们能够为我们的机械化提供支持， 假设，并确定烟草暴露与时间变化之间的关系， HPV+OPSCC。最后，我们将比较HPV+OPSCC肿瘤的时间特征， 对HPV+OPSCC的TIME常规放化疗方案无效 对治疗有反应的肿瘤，以确定与以下相关的免疫特征： 治疗耐药性在这个疾病的网站（目的3）。总之，这些实验将使我们能够：1） 定义烟草暴露维斯HPV+OPSCC生存率的临床相关效应量，以及2） 开始确定烟草暴露和时间依赖性治疗之间的机制联系 反应成功完成拟议的研究将使我们能够更适当地 预测HPV+OPSCC退伍军人的生存率，确定可能的候选患者 对于使用免疫调节剂（即检查点抑制剂）的治疗递增， 不应参加旨在降低放化疗方案的临床试验 以降低正常组织毒性。 在进行拟议研究的同时，主要研究者将参加培训 旨在在流行病学领域提供更多设施和专业知识的活动， 生物统计学以及肿瘤免疫学，通过正式和在线课程的结合 工作，参加机构、地方和国家会议，并与 导师委员会在这3个癌症研究领域具有适当的专业知识。

Oropharyngeal cancer is rapidly increasing in incidence in the veteran population, fueled largely by exposure to the human papilloma virus (HPV). Although survival for oropharyngeal squamous cell carcinoma associated with the human papilloma virus (HPV+OPSCC) is excellent in the general population, it remains dismal in the veteran population, with nearly 1 in 2 patients dying of their disease within 5 years of diagnosis. This disproportionally poor survival is thought to be driven in part by tumors which are less responsive to chemo-radiation treatment regimens. Preliminary data from our group and others suggests this decreased treatment response may be in part driven by tobacco exposure, which is extremely prevalent among Veterans with HPV+OPSCC. The hypothesized mechanism of action is a tobacco induced, immunosuppressive environment which inhibits the normal anti-tumor activity of lymphocytes and other immune cells during cancer treatment. In the current proposal, we will first characterize and quantify the relative effect of tobacco exposure on survival in Veterans with HPV+OPSCC (Aim 1). This is critical in light of the newly implemented 8th Edition of the AJCC Staging Manual which dramatically down-stages OPSCC based on HPV status (HPV associated vs non-HPV associated), but does not consider the potentially critical impact of tobacco exposure on survival. Given the widespread, and extensive tobacco exposure we and others have demonstrated in Veterans with OPSCC, this represents an important clinical and translational first step in potentially improving survival for Veterans with this disease. We will then characterize the Th1 T-lymphocyte and myeloid derived suppressor cell (MDSC) components of the tumor immune microenvironment (TIME) in HPV+OPSCC tumors as a function of tobacco exposure (Aim 2). This will allow us to provide support for our mechanistic hypothesis and to define the relationship between tobacco exposure and changes in the TIME of HPV+OPSCC. Finally, we will compare the TIME characteristics of HPV+OPSCC tumors which fail to respond to conventional chemo-radiation treatment regimens to the TIME of HPV+OPSCC tumors which do respond to treatment, in order to define an immune signature associated with treatment resistance in this disease site (Aim 3). Together, these experiments will allow us to: 1) define a clinically relevant effect size for tobacco exposure vis a vis HPV+OPSCC survival and 2) begin to define a mechanistic link between tobacco exposure and TIME dependent treatment response. Successful completion of the proposed research will allow us to more appropriately prognosticate survival in Veterans with HPV+OPSCC, identify patients which may be candidates for treatment escalation using immunomodulatory agents (i.e. checkpoint inhibitors) and patients which should not be enrolled in clinical trials aimed at de-escalation of chemo-radiation regimens in order to decrease normal tissue toxicity. In parallel with the proposed research, the Principal Investigator will engage in training activities designed to provide increased facility and expertise in the areas of Epidemiology and Biostatistics as well as Tumor Immunology, through a combination of formal and online course work, participation in institutional, local and national meetings and direct interactions with a Mentorship Committee with appropriate expertise in these 3 areas of cancer research.