Abstract 509: Acarbose, but not metformin, reduces tumor burden and improves intra-tumoral immune responses in a pre-clinical breast cancer model

Abstract

Abstract Finding ways to enhance T cell infiltration into tumors and boost effector function remains a critical knowledge gap that must be addressed to improve responses to immune-stimulatory therapies. Acarbose and metformin are FDA-approved drugs for the treatment of type two diabetes that display potent anti-hyperglycemic activity. A treatment strategy that decreases intra-tumoral glucose could reduce cancer cell viability and render tumors more susceptible to immunotherapy-mediated clearance. The goal of the current study was to determine if acarbose and/or metformin reduce tumor burdens and promote anti-tumor immunity in a preclinical model of breast cancer. Eight-week-old female C57BL/6 mice were orthotopically injected with EO771-Fluc mammary tumor cells then randomized to control (CTRL), CTRL+acarbose (ACA), CTRL+metformin (MET), or acarbose+metformin (ACA+MET) for four weeks. Compared to CTRL, single-agent ACA reduced primary tumor growth (50% decrease; p<0.001) and spontaneous lung metastases (48% decrease; p=0.035) without altering body weight. No effects of single-agent MET or the combination of ACA+MET on EO771 tumor growth or spontaneous lung metastases were observed. nanoString analysis of whole-tumors revealed increased dendritic cell-, T cell-, T helper 1 cell-, CD8+ T cell-, and exhausted CD8+ T cell-based gene signature scores in ACA compared to CTRL-fed mice. Cellular analysis revealed an ACA-induced increase in the percent of tumor-infiltrating PD-1+CD8+ T cells (p=0.042) and a trend toward decreased tumor-infiltrating myeloid-derived suppressor cells, resulting in improved CD8:MDSC ratios. The beneficial effects of ACA on intra-tumoral immunity, specifically promoting T cell immunity within the tumor microenvironment, illustrate the potential for future combined use of ACA with immunotherapies, such as PD-1 or CTLA-4 blockade. Citation Format: William J. Turbitt, Rachael M. Orlandella, Justin T. Gibson, Lyse A. Norian. Acarbose, but not metformin, reduces tumor burden and improves intra-tumoral immune responses in a pre-clinical breast cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 509.