Background: Obesity leads to a higher risk of cancer invasion, metastases, recurrence, mortality, and impaired therapeutic response through various mechanisms. One of these mechanisms is microenvironment dysfunction, where changes in immune cells, microbes, metabolites, and growth factors contribute to tumor aggressiveness. We study obesity-induced changes to the tumor microenvironment in Triple Negative Breast Cancer (TNBC), an aggressive subtype associated with obesity. The goal to compare tumor progression in lean vs. obese vs. weight loss manipulations to identify causal and targetable pathways associated with reprogramming the tumor microenvironment. Clinically, bariatric surgery induced weight loss reduced the risk of BC, with the greatest benefit detected in pre-menopausal patients with ER- tumors, like TNBC. We hypothesize surgically-induced weight loss will diminish obesity-associated tumor progression. Methods: To study weight gain and loss that best mimics human adiposity, we utilized obesogenic C57BL/6 females with a syngeneic orthotopic transplant of TNBC cells. Female mice placed on a high fat diet (HFD) at weaning became obese compared to mice on a low fat diet (LFD). After 16 weeks on an HFD diet, mice underwent the bariatric surgery Vertical Sleeve Gastrectomy (VSG). The VSG resulted in reduced body weight, adiposity, and correction of metabolic profiles compared to obese mice. Two weeks post-surgery, TNBC cells were OT into the mammary fat. Results: As expected, tumor growth was increased in obese mice compared to lean. Importantly, surgical weight loss rescued obese tumor progression. We identified key changes in tumor infiltrating of immune cells that could be responsible for the beneficial effects of bariatric surgery on tumor progression. We then exploited these changes with immunotherapy, which was uniquely effective in mice that underwent bariatric surgery. Conclusions: In conclusion obesity promotes a pro-tumor microenvironment, that can be corrected through surgically induced weight loss.
Citation Format: Laura Sipe, Mehdi Chaib, Emily B Korba, Mary C Lovely, Jared C Clements, Neena A John, Ajeeth K Pingili, Joseph F Pierre, Liza Makowski. Surgically induced weight loss corrects obesity associated tumor progression and improves responsiveness to immunotherapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-29.