Prognostic Impact of DPP4 Inhibitors on Systemic Drug Therapy for Advanced Kidney Cancer Patients

Unmet challenges in systemic therapy persist for advanced renal cell carcinoma (RCC) despite the widespread use of anti-angiogenetic tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). We previously showed that dipeptidyl peptidase 4 inhibitor (DPP4i) improved TKI sensitivity using patient-derived RCC cells and experimental TKI-resistant models. To address whether DPP4i is clinically useful for the enhancement of RCC systemic therapy, including ICIs, we analyzed 320 cases with RCC who underwent systemic therapy. Patients with DPP4i treatment exhibited longer overall survival (hazard ratio: 0.50, 95% confidence interval: 0.30-0.82, p = 0.0060). In the Cox proportional hazards model, the use of DPP4is, along with BMI ≥ 25, no metastasis, low serum lactate dehydrogenase (LDH), and low serum C-reactive protein (CRP), was a favorable prognostic factor. Additionally, more pronounced tumor shrinkage was observed in a within-subgroup comparison of patients receiving TKI or ICI as first-line therapies. Consistently, we found that DPP4 high RCC tumors exhibit reduced immune infiltration and lower scores for effector T cell infiltration-related signatures based on the RNA sequencing data from the CheckMate-009, 010, and 025 studies. These findings can potentially change the interpretation of the prognostic impact of type 2 diabetes mellitus on RCC and bolster the rationale for initiating a prospective clinical trial to evaluate concurrent use of DPP4i with RCC therapeutic strategies.