Abstract 1260: Diet and exercise-induced weight maintenance may be preventing mammary tumor growth and metastatic burden by enhancing antitumor immunity and/or reducing protumorigenic factors

Abstract

Abstract Two lifestyle factors that increase cancer risk and progression are weight gain and sedentary behavior. Possible mechanisms underlying this relation include changes in metabolic, inflammatory, and immune mediators. Few studies have examined the effect of body weight and exercise on the efficacy of immunotherapeutic strategies. An emerging immunotherapeutic strategy is PD-1 checkpoint blockade, which selectively targets the membrane protein programmed cell death-1 (PD-1) on T cells to promote a sustained, antitumor effector response. Thus, the goal of the current study was to determine if preventing weight gain through diet (10% reduction in calories) and exercise (voluntary running wheel activity) will improve the response to the dual administration of a whole tumor cell vaccine and PD-1 checkpoint blockade. Female BALB/c mice were randomized to sedentary, weight gain (WG) or exercising, weight maintenance (WM) groups (n=32/group). After 8 weeks, all mice were orthotopically injected with 5x104 luciferase-transfected 4T1.2 cells into the fourth mammary fat pad and continued on their intervention for 35 days. After injection, WG and WM mice were randomized into vaccination (VAX) or vehicle (VEH) groups, and 1x106 irradiated 4T1.2 cells or HBSS vehicle control, respectively, was administered at day 7 post-tumor injection. Mice were further randomized (n=8/group) to receive anti-PD-1 (10 mg/kg/mouse) or isotype control at day 9 and 12 post-tumor injection. All WM groups, regardless of immunotherapy intervention, weighed significantly less than WG groups over the course of the study (p<0.001). Mean tumor volume (p<0.001) and tumor weight at sacrifice (p=0.076) were significantly lower with PD-1 treatment in the WG but not WM groups. Furthermore, metastatic burden in the lung (p=0.032) and the number of splenic myeloid-derived suppressor cells (p=0.058) was reduced with VAX+PD-1 treatment in the WG but not WM groups. Thus, the combination of VAX+PD1 was effective at reducing primary tumor growth and metastatic burden and improving immune outcomes only in mice that gained weight over the course of the study. However, diet and exercise alone was effective in reducing tumor growth and metastatic burden. The lack of responsiveness to vaccination + anti-PD-1 treatment in WM mice suggests that WM achieved through diet and exercise may be enhancing antitumor immunity and/or reducing protumorigenic factors (i.e. similar mechanisms mediated by vaccination + anti-PD-1 therapy). These data demonstrate that preventing weight gain through diet and exercise may be an important recommendation to maintain prolonged antitumor effector responses and improve clinical outcomes. Citation Format: William J. Turbitt, Yitong Xu, Andrea M. Mastro, Connie J. Rogers. Diet and exercise-induced weight maintenance may be preventing mammary tumor growth and metastatic burden by enhancing antitumor immunity and/or reducing protumorigenic factors [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 1260. doi:10.1158/1538-7445.AM2017-1260