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

 描述（由申请方提供）：人乳头状瘤病毒（HPV+）相关口咽鳞状细胞癌（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使用暴露于放化疗的HPV+ OPSCC的同基因小鼠模型来阐明肿瘤和癌症治疗如何诱导症状以及可以做些什么来预防症状的发展。由于癌症相关症状和炎症诱导疾病的行为体征之间的强烈相似性，工作假设是对HPV+ OPSCC和细胞毒性治疗的炎症反应传播到大脑并激活疾病的神经元回路。该假设将在3个特定目的中进行测试，这些特定目的设计为：（1）表征疾病发展与外周和中枢炎症的时间进程之间的关联，并确定植入HPV+阳性肿瘤细胞并暴露于放化疗的小鼠中小胶质细胞活化的状态;（2）通过关注炎症的触发因素和介质，确定引起肿瘤和放化疗相关疾病的分子因素，包括损伤相关分子模式（DAMP）和细胞因子信号传导途径;和（3）确定细胞因子信号传导途径下游的犬尿氨酸途径的激活是否有助于放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DAMP释放到疾病神经元回路募集的事件链中寻找可药物化的靶点，这些靶点不会影响肿瘤清除和存活。HPV+ OPSCC的发病率不断增加，而HPV-OPSCC的发病率则稳步下降。HPV+ OPSCC主要影响处于生命高峰期的个体，给受影响的个体和社会带来巨大的成本。确定缓解症状负担和促进恢复正常日常功能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.