Elucidating the impacts of body composition and physical activity on anti-tumor immunity and cancer control in advanced stage high-grade serous carcinoma

High-grade serous ovarian carcinoma (HGSOC) is a quintessential example of a highly fatal malignancy that has not greatly benefited from therapeutic or screening advances in oncology. As symptoms are vague, 75% of patients are diagnosed at late stage, and most will recur with chemo-resistant disease within three years. Although it is well recognized that tumor immunity plays a critical role in the pathogenesis of HGSOC, nearly 85% of patients don’t respond to immunotherapy and comprehensive interrogation of the HGSOC tumor immune microenvironment (TIME) remains preliminary, wherein optimal patterns of immune infiltration and spatial relationships have not been well defined. At present, clinical characteristics (age at diagnosis, tumor stage, presence of ascites, and debulking status) are the only established prognostic factors and little is known about the impacts of modifiable lifestyle exposures, and related immune biomarkers, in improving HGSOC survival. Despite consistent recommendations from leading organizations to adhere to healthy lifestyles during cancer treatment and survivorship, which lifestyle factors, and whether they work together to improve treatment and survival outcomes remains a fundamental unanswered question. Moreover, whether lifestyle interventions during active therapy are associated with improved treatment and survival outcomes remains unknown. To this end, an emerging body of pre-clinical evidence from a variety of animal models suggests the TIME is highly plastic and modulated by unhealthy host exposures including obesity and inactivity via metabolic and immune dysregulation, while voluntary wheel running enhances anti-tumor immunity, increases infiltration of cytotoxic immune cells and mitigates entry of immune-suppressive cells into the tumor. Although compelling, our current understanding of how obesity and physical activity (PA) impact immunity in patients is mostly limited to circulating markers, which may not reflect the TIME, the most relevant site for tumor progression and prognosis. Herein, we contend that optimal body composition and regular PA in the peri-diagnosis period are associated with improved survival in advanced-stage HGSOC, and that these associations are mediated by enhanced immunity in the TIME. To test this hypothesis, we will use the high throughput PhenoCycler platform to assess 15 immune subsets in FFPE tumor sections from 500 patients diagnosed with advanced-stage HGSOC from Roswell Park and Moffitt Comprehensive Cancer Centers for linkage with lifestyle, epidemiological and clinical data. Leveraging multi-scale spatial analyses and formal mediation pathway analysis we propose the following three Specific Aims: 1) Define associations of body composition and physical activity in the peri-diagnosis period with immune cell abundance and spatial distributions (the immune contexture) in the HGSOC TIME; 2) Identify associations of immune cell abundance and spatial distributions in the TIME with HGSOC survival; and 3) Delineate the associations of body composition and physical activity with improved HGSOC survival into direct and indirect (mediating) pathways relayed through the tumor immune contexture. Project Number: 1R37CA312294-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Rikki Cannioto | Institution: ROSWELL PARK CANCER INSTITUTE CORP, BUFFALO, NY | Award Amount: $713,312 | Activity Code: R37 | Study Section: Cancer and Hematologic Disorders Study Section[CHD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11344511