Harnessing Dietary n-3 Fatty Acids to Unleash Protective Immunity Against Ovarian Cancer
Abstract
Standard treatments based on surgery and chemotherapy demonstrate limited success in ovarian cancer, and the 5-year survival rate for patients with metastatic disease remains lower than 30%. It is estimated that ovarian cancer will claim more than 14,000 deaths in the United States in 2020. Thus, new and more effective therapeutic strategies are urgently needed. Harnessing the immune system to eliminate tumors, termed immunotherapy, is an attractive approach to complement conventional cancer treatments. Immunotherapy has benefited patients with certain types of cancer including melanoma and lung carcinoma. Yet, ovarian cancer patients remain refractory to this modality. Importantly, whether specific dietary habits affect the immune response to ovarian cancer and/or the efficacy of immunotherapy in this malignancy remains unknown. Our project seeks to determine whether dietary lipids modulate the progression of metastatic ovarian cancer by altering the protective function of the immune system. In preliminary studies, we found that a diet rich in n-3 (omega-3, fish oil) fatty acids significantly extended survival in ovarian cancer-bearing mice, compared with diets enriched in either saturated fatty acids (lard) or n-6 fatty acids (corn oil). Of note, the diet-specific increase in survival was accompanied by decreased metastasis to the omentum, enhanced intratumoral infiltration by activated immune cells, and alterations in the intestinal microbial composition. These key findings provided a strong rationale to investigate the mechanisms underlying the protective effects of n-3 fatty acids on the course of ovarian cancer. Hence, the goals of this proposal are to (1) understand how dietary lipids modulate endogenous immune responses to ovarian tumors, (2) define whether these dietary lipids alter the intestinal microbiota to limit ovarian cancer progression, and (3) establish that a diet rich in n-3 fatty acids can be exploited to enhance the efficacy of treatment with PARP inhibitors and immunotherapy in ovarian cancer. Our work will provide a key mechanistic rationale for future human studies focused on practical lifestyle interventions, such as specific diet modifications, that inherently boost endogenous immunity to ovarian cancer. Diet is an integral component of the management of patients with both diabetes and cardiovascular disease. Nevertheless, detailed dietary guidelines for ovarian cancer patients have not been established, and it remains unknown whether tailored nutritional interventions could improve the efficacy of targeted therapies or immune-based treatments in women afflicted by this malignancy. Since our project focuses on harnessing dietary n-3 lipids to improve the immunotherapeutic effects of PARP inhibitors and checkpoint blockade, our findings could have immediate clinical applicability towards eliminating ovarian cancer, thus positively impacting the wellness of thousands of patients and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110357
Entities
People
- Juan R Cubillos-Ruiz
Organizations
- United States Army
- Weill Cornell Medicine