Improving Treatment Algorithms for Veterans with Oropharyngeal Cancer

口咽癌在退伍军人中的发病率迅速上升， 主要是由于接触了人乳头瘤病毒(HPV)。虽然口咽部的存活 与人乳头瘤病毒(HPV+OPSCC)相关的鳞状细胞癌是很好的 在普通人群中，退伍军人的情况仍然令人沮丧，几乎每2名患者中就有1人 在确诊后5年内死于疾病。这种不成比例的生存状况被认为是 这在一定程度上是由对化疗-放射治疗方案反应较差的肿瘤推动的。 来自我们小组和其他人的初步数据表明，这种治疗反应降低可能是 部分原因是吸烟，这在退伍军人中非常普遍， HPV+OPSCC。假想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正常抗肿瘤活性的环境 在癌症治疗期间。 在目前的提案中，我们将首先描述和量化烟草的相对影响 HPV+OPSCC对退伍军人生存的影响(目标1)。鉴于新的 实施了AJCC分级手册第8版，大大降低了OPSCC的级别 基于HPV状态(关联HPV与非关联HPV)，但不考虑 烟草暴露对生存的潜在严重影响。考虑到广泛的、广泛的 我们和其他人在患有OPSCC的退伍军人中展示了烟草暴露，这代表了一种 这是潜在改善退伍军人存活率的重要临床和转化性第一步 疾病。 然后我们将鉴定Th1 T淋巴细胞和髓系来源的抑制细胞 HPV+OPSCC肿瘤中肿瘤免疫微环境(TIME)成分(MDSC) 烟草暴露的作用(目标2)。这将使我们能够为我们的机械设备提供支持 假说，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 常规放化疗方案对HPV+OPSCC无效 对治疗有反应的肿瘤，以定义与 本病区的抗药性(目标3)。总之，这些实验将使我们能够：1) 确定烟草暴露与HPV+OPSCC生存率的临床相关效应大小和2) 开始确定烟草暴露和依赖时间的治疗之间的机械联系 回应。成功完成拟议的研究将使我们能够更恰当地 预测HPV+OPSCC退伍军人的存活率，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)和患者的治疗升级 不应纳入旨在降低化疗放射方案升级的临床试验 以降低正常组织毒性。 在进行拟议研究的同时，首席调查员将参加培训 旨在提供更多流行病学和专门知识领域设施和专业知识的活动 生物统计学和肿瘤免疫学，通过正式课程和在线课程相结合 工作，参与机构、地方和国家会议，并与 在这三个癌症研究领域拥有适当专业知识的导师委员会。

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.