Abstract 243: Diet and exercise-induced weight maintenance, alone and in combination with a whole tumor cell vaccine, delays mammary tumor growth and reduces MDSC accumulation

Abstract

Abstract Obesity and physical inactivity increase breast cancer risk, while the prevention of weight gain by diet and exercise can be protective. Numerous biological mechanism(s) have been proposed to explain the beneficial effects of weight maintenance; however few studies have examined the immune response to energy balance. We have previously shown that diet and exercise-induced weight maintenance (WM) achieved via a 10% restriction in calories and access to voluntary running wheels in combination with a whole tumor cell vaccine (VAX) significantly reduced mammary tumor growth and metastases in the 4T1 mammary tumor model. This WM-induced reduction in tumor growth occurred concurrently with an elevation in tumor specific IFN-γ production and a reduction in the number of myeloid-derived suppressor cells (MDSCs). However, because tumor size is positively correlated with immune suppression, the goal of the current study was to investigate if mice in the WM+VAX intervention had enhanced anti-tumor immune responses and/or fewer MDSCs controlling for tumor size. Female BALB/c mice were randomized into weight gain (WG) and WM groups (n=8/group) and had access to voluntary running wheels or standard cages, respectively. WG mice were fed ad libitum while WM mice were energy-restricted by 10% to maintain a stable body weight. After 8 weeks on the intervention, all mice were orthotopically injected with 5x104 4T1.2 cells into the fourth mammary fat pad and continued on their intervention. Once injected, both WG and WM mice were further randomized into vaccination (VAX) and vehicle control (VEH) groups (n=4/gr) and administered 1x106 irradiated 4T1.2 cells (VAX) or HBSS (VEH) at day 7 post-tumor implantation. Primary tumor growth was quantified, and mice were sacrificed when tumor volume reached 0.1-0.2 cm3. WM mice weighed significantly less than WG mice over the course of the study (p<0.001). Mice in both WM+VEH and WM+VAX groups took a significantly longer number of days post tumor implantation to reach a tumor size of 0.1-0.2 cm3 (26.3 ± 3.3 d, p=0.003; 23.8 ± 0.5 d, p=0.039, respectively) compared to the WG+VEH group (18.3 ± 2.5 d). Despite the fact that mice were sacrificed when the tumor volumes were standardized at 0.1-0.2 cm3, the combination of WM+VAX resulted in a significant reduction of splenic MDSC accumulation (p=0.049) and enhanced CD4+ T cell proliferation ex vivo. These results suggest that diet and exercise-induced WM was highly effective in delaying primary mammary tumor growth. The combination of WM and an allogenic whole tumor cell vaccine reduced pro-tumorigenic MDSC accumulation and enhanced effector T cell function. Furthermore, these data suggest that diet and exercise may be changing the tumor microenvironment at an early stage of tumor growth favoring tumor clearance. This work is supported by R21 CA209144; T32AI074551. Citation Format: Yitong Xu, William J. Turbitt, Andrea M. Mastro, Connie J. Rogers. Diet and exercise-induced weight maintenance, alone and in combination with a whole tumor cell vaccine, delays mammary tumor growth and reduces MDSC accumulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 243. doi:10.1158/1538-7445.AM2017-243