Acarbose Delays Renal Cancer Progression in Mice: Implications for Obesity‐Induced Immunotherapeutic Failure

Abstract

Obesity is a regarded as a major risk factor for developing renal cell carcinoma (RCC). Advanced‐stage RCC exhibits chemotherapeutic resistance, but is responsive to high‐dose IL‐2 and anti‐PD‐1 immunotherapies. Despite successes in these treatments, response rates remain low (20–30%). Currently, pre‐clinical evaluations of immunotherapeutic strategies typically use lean, young mice and do not account for the presence of patient comorbidities. This may partially explain the underwhelming success in clinical translation. Our laboratory previously demonstrated that a T cell‐based immunotherapy clears orthotopic renal tumors in lean mice, but fails in diet‐induced obese mice. This illustrates the importance of identifying methods to rescue obesity‐induced immunotherapeutic failure in this model. Calorie restriction (CR) delays the onset of chronic diseases, such as obesity and cancer. This attribute has prompted interest in investigating CR and its substitutes as potential cancer therapeutics. Recent murine research shows that diets containing calorie restriction mimetics (CRMs) improve anti‐tumor immunity and chemotherapeutic efficacy. Here we examined acarbose, an α‐glucosidase inhibitor with CRM properties, in a preclinical model of kidney cancer. BALB/c mice were fed an acarbose‐supplemented or control diet following orthotopic tumor challenge with syngeneic Renca renal carcinoma cells. Acarbose reduced endpoint tumor weights (p=0.02) and lung metastases (p=0.03). Flow cytometric analysis at endpoint revealed similar frequencies of splenic and intra‐tumoral CD8 T cells in mice treated with acarbose. These findings suggest that acarbose may exhibit anti‐tumor properties, and indicates a potential treatment opportunity for mice with diet induced obesity. Future experiments will focus on evaluating acarbose in combination with immunotherapy, in lean and obese mice.Support or Funding InformationT32HL105349This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.