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.