Neuroimmune Mechanisms of Cancer-Related Symptoms in Oral Squamous Cell Carcinoma

 描述(申请人提供)：与人乳头瘤病毒(HPV+)相关的口咽鳞状细胞癌(OPSCC)患者在癌症治疗过程中会出现严重的全身症状，包括疲劳、抑郁和认知功能障碍。这些症状对生活质量产生负面影响，并损害他们的日常社会和职业功能，即使在停止治疗后也是如此。该项目的长期目标是利用HPV+OPSCC的同基因小鼠模型，阐明肿瘤和癌症治疗是如何导致症状的，以及可以做些什么来防止症状的发展。由于癌症相关症状和炎症诱发疾病的行为体征之间有很强的相似性，工作假说是对HPV+OPSCC和细胞毒治疗的炎症反应传播到大脑并激活疾病的神经回路。这一假说将被验证在3个特定的目标旨在：(1)表征疾病的发展和外周和中心炎症的时间病程之间的联系，并确定小鼠的小胶质细胞的激活状态；(2)通过专注于炎症的触发和介质，包括损伤相关的分子模式(DAMP)和细胞因子信号通路，确定导致肿瘤和化疗相关疾病的分子因素；(3)确定细胞因子信号通路下游的犬尿氨酸途径激活是否参与了化疗诱导的疾病的发展。由于宿主的免疫系统参与了放化疗诱导的OPSCC清除，特别是在HPV+肿瘤中，我们将在从释放潮湿到疾病神经元回路招募的一连串事件中寻找可用药的靶点，这些事件不会影响肿瘤的清除和存活。HPV+OPSCC的发病率上升，而HPV-OPSCC的发病率稳步下降。HPV+OPSCC主要影响处于人生生产高峰期的个人，给受影响的个人和社会带来巨大代价。查明减轻症状负担和促进恢复正常日常运作的方法将对个人和社会产生重要的积极影响。

 DESCRIPTION (provided by applicant): Patients with human papilloma virus (HPV+)-related oropharyngeal squamous cell carcinoma (OPSCC) experience severe systemic symptoms including fatigue, depression, and cognitive dysfunction during the course of cancer therapy. These symptoms negatively affect quality of life and compromise their daily social and vocational functioning, even after cessation of therapy. The long-term goal of this project is to elucidate, using a syngeneic murine model of HPV+ OPSCC exposed to chemoradiation, how the tumor and cancer therapy induce symptoms and what can be done to prevent symptom development. Because of the strong analogy between cancer-related symptoms and the behavioral signs of inflammation-induced sickness, the working hypothesis is that the inflammatory response to HPV+ OPSCC and to cytotoxic therapy propagates to the brain and activates the neuronal circuitry of sickness. This hypothesis will be tested in 3 specific aims designed to: (1) characterize the association between the development of sickness and the time course of peripheral and central inflammation, and determine the status of microglia activation in mice implanted with HPV+ positive tumor cells and exposed to chemoradiation; (2) identify the molecular factors that cause tumor- and chemoradiation-associated sickness by focusing on triggers and mediators of inflammation, including damage-associated molecular patterns (DAMPs) and cytokine signaling pathways; and (3) determine whether activation of the kynurenine pathway downstream of cytokine signaling pathways contributes to the development of chemoradiation-induced sickness. Because the immune system of the host is involved in chemoradiation-induced clearance of OPSCC especially in HPV+ tumors, we will search for druggable targets in the chain of events leading from the release of DAMPs to the recruitment of neuronal circuits of sickness that do not compromise tumor clearance and survival. There is an increasing incidence rate of HPV+ OPSCC that contrasts with steady declines in HPV-OPSCC. HPV+ OPSCC predominantly affects individuals at peak productive points in their lives, with enormous costs to affected individuals and the society. Identification of means to alleviate symptom burden and facilitate the return to normal daily functioning will have an important positive individual and societal impact.