Abstract 2240: Diet and exercise-induced weight maintenance, alone and in combination with a whole tumor cell vaccine, delays mammary tumor growth and reduces tumor-infiltrating MDSCs expressing PD-L1 and IDO

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 mechanisms are proposed to explain the beneficial effects of weight maintenance, including changes in metabolic, inflammatory and immune mediators. We have previously shown that diet and exercise-induced weight maintenance (WM), in combination with a whole 4T1.2luc tumor cell vaccine (VAX), significantly reduced mammary tumor growth and metastases in the 4T1.2luc murine mammary tumor model. This reduction in growth and metastases occurred concomitantly with an elevation in tumor antigen-induced splenic IFN-γ production and a reduction in the accumulation of splenic myeloid-derived suppressor cells (MDSCs) at day 35 post-tumor implantation. The goal of the current study was to determine if WM+VAX alters the tumor microenvironment at an early stage of tumor growth (day 24 post-tumor implantation) which may contribute to reduced tumor growth and enhanced immune outcomes at day 35 post-tumor implantation. Female BALB/c mice were randomized into sedentary, weight gain (WG) or exercising (access to voluntary running wheel), weight maintenance (WM) groups (n=22-27/group). After 8 weeks on the intervention, all mice were orthotopically injected with 5x104 4T1.2luc 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) or vehicle control (VEH) groups (n=10-15/group) and administered 1x106 irradiated 4T1.2luc cells (VAX) or HBSS (VEH) at day 7, 14 and 21 post-tumor implantation. Mice were sacrificed at day 24 post-tumor implantation and tumor-infiltrating immune cells were isolated for analyses. Both WM+VEH and WM+VAX groups showed a significant reduction in primary tumor growth and splenomegaly compared to both WG groups (p<0.001). Flow cytometric analysis demonstrated that the combination of WM+VAX significantly reduced total tumor-infiltrating MDSCs and MDSCs expressing PD-L1 and indoleamine 2,3-dioxygenase (IDO) compared to WG+VEH (p<0.05). This finding was consistent with a 1.5-4.5 fold decrease in the gene expression level of Pdcd1, Ido1 and Ifng in the total tumor infiltrates. These results suggest that the combination of weight maintenance and the whole tumor cell vaccine may be altering both the number and immunosuppressive capacity of tumor-infiltrating MDSCs. Thus, preventing weight gain through diet and exercise may be an important recommendation in combination with immune-based therapies to enhance efficacy and improve clinical outcomes. This work is supported by R21 CA209144; T32GM108563. W.J.T is currently funded by the NIH T32DK062710 grant; NORC, UAB, Birmngham, AL. 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 tumor-infiltrating MDSCs expressing PD-L1 and IDO [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2240.