Although immune checkpoint inhibitors and targeted therapeutics have changed the landscape of treatment for renal cell carcinoma (RCC), most patients do not experience significant clinical benefits. Emerging preclinical studies report that nutrition-based interventions and glucose-regulating agents can improve therapeutic efficacy. However, the impact of such agents on therapeutic efficacy in metastatic kidney cancer remains unclear. Here, we examined acarbose, an alpha-glucosidase inhibitor and antidiabetic agent, in a preclinical model of metastatic kidney cancer. We found that acarbose blunted postprandial blood glucose elevations in lean, nondiabetic mice and impeded the growth of orthotopic renal tumors, an outcome that was reversed by exogenous glucose administration. Delayed renal tumor outgrowth in mice on acarbose occurred in a CD8 T cell-dependent manner. Tumors from these mice exhibited increased frequencies of CD8 T cells that retained production of IFNγ, TNFα, perforin, and granzyme B. Combining acarbose with either anti-PD-1 or the mammalian target of rapamycin inhibitor, rapamycin, significantly reduced lung metastases relative to control mice on the same therapies. Our findings in mice suggest that combining acarbose with current RCC therapeutics may improve outcomes, warranting further study to determine whether acarbose can achieve similar responses in advanced RCC patients in a safe and likely cost-effective manner.

Associations between modifiable factors and the efficacy of cancer immunotherapies remain uncertain. We found previously that diet-induced obesity (DIO) reduces the efficacy of an immunotherapy consisting of adenovirus-encoded TRAIL plus CpG oligonucleotide (AdT/CpG) in mice with renal tumors. To eliminate confounding effects of diet and determine whether outcomes could be improved in DIO mice, we evaluated AdT/CpG combined with anti-CTLA-4 in diet-matched, obese-resistant (OB-RES) versus DIO tumor-bearing mice. Therapy-treated OB-RES mice displayed effective renal tumor control and sustained CD4⁺ and CD8⁺ T cell responses. In contrast, therapy-treated DIO mice exhibited progressive tumor outgrowth and blunted T cell responses, characterized by reduced intratumoral frequencies of IFNγ⁺ CD4⁺ and CD8⁺ T cells. Weak effector T cell responses in therapy-treated DIO mice were accompanied by low intratumoral concentrations of the T cell chemoattractant CCL5, heightened concentrations of pro-tumorigenic GM-CSF, and impaired proliferative capacity of CD44⁺CD8⁺ T cells in tumor-draining lymph nodes. Our findings demonstrate that in lean mice with renal tumors, combining in situ T cell priming upstream of anti-CTLA-4 enhances outcomes versus anti-CTLA-4 alone. However, host obesity is associated with heightened immunotherapy resistance, characterized by multi-factorial deficiencies in effector CD4⁺ and CD8⁺ T cell responses that extend beyond the tumor microenvironment.

Commentary: Predictors of Colorectal Cancer Screening in Two Underserved U.S. Populations: A Parallel Analysis

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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 Information T32HL105349 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .