The Antidiabetic Agent Acarbose Improves Anti-PD-1 and Rapamycin Efficacy in Preclinical Renal Cancer

Abstract

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.

A Novel Nine Apoptosis-Related Genes Signature Predicting Overall Survival for Kidney Renal Clear Cell Carcinoma and its Associations with Immune Infiltration

“…However, almost one third of these newly diagnosed patients had metastases and a poor prognosis ( Dagher et al, 2017 ). Although targeted therapeutics and immune checkpoint inhibitors have changed the landscape of treatment for ccRCC, most patients still did not experience significant clinical benefits ( Orlandella et al, 2020 ). Accordingly, it was critical to discover more effective methods for early screening and diagnosis of ccRCC by further understanding its molecular mechanism and biological process.…”

TF–RBP–AS Triplet Analysis Reveals the Mechanisms of Aberrant Alternative Splicing Events in Kidney Cancer: Implications for Their Possible Clinical Use as Prognostic and Therapeutic Biomarkers

“…Despite early surgical treatment, 30% of patients with a localized tumor eventually develop metastases, and the five-year overall survival rate of metastatic KIRC is only 12% [2][3][4]. Although immune-checkpoint and targeted therapeutics inhibitors have changed the landscape of treatment for KIRC, most patients have never experienced significant clinical benefits [5,6]. Therefore, it is essential to reveal the underlying molecular mechanisms of KIRC and find more powerful diagnostic biomarkers or therapeutic targets.…”

Diet-Induced Obesity Impairs Outcomes and Induces Multi-Factorial Deficiencies in Effector T Cell Responses Following Anti-CTLA-4 Combinatorial Immunotherapy in Renal Tumor-Bearing Mice

“…Time-restricted feeding differentially impacted tumor growth with older, HFD-fed mice experiencing reduced renal tumor bioluminescence; however, time-restricted feeding did not alter tumor weights or intratumoral immune responses and failed to improve anti-CTLA-4 monotherapy [ 52 ]. Acarbose delayed renal tumor growth in a CD8 + T cell-dependent manner, increasing the abundance and maintaining the effector function CD8 + TILs [ 53 ]. When combined with αPD-1, acarbose significantly reduced lung metastasis, suggesting that combining acarbose with current therapies may improve outcomes [ 53 ].…”

“…Acarbose delayed renal tumor growth in a CD8 + T cell-dependent manner, increasing the abundance and maintaining the effector function CD8 + TILs [ 53 ]. When combined with αPD-1, acarbose significantly reduced lung metastasis, suggesting that combining acarbose with current therapies may improve outcomes [ 53 ]. Lastly, it would be of interest to determine whether weight loss could reverse the obesity-induced immunological deficiencies and improve response to combinatorial immunotherapy.…”