823 Repurposing CD26/DPP4 inhibitors to enhance immunotherapy response in pancreatic ductal adenocarcinoma

BackgroundPancreatic ductal adenocarcinoma (PDAC) features a fibrotic stroma that obstructs immune infiltration. We hypothesize that dysregulated CD26/DPP4 enzymatic activity in PDAC constrains the efficacy of immunotherapy. We also posit that in vivo pharmacological targeting of CD26 enzyme activity, via FDA-approved inhibitors (sitagliptin or STG) for Type 2 Diabetes, influences immune infiltration and enhances immunotherapy response in murine PDAC models.MethodsCD26 protein was evaluated in immortalized cancer associated fibroblasts (CAFs) and PDAC cells by immunoblot and flow, while soluble CD26 was measured by ELISA. In vivo studies used C57BL/6 mice orthotopically implanted with syngeneic luciferase-expressing KPC-tumor cells in the pancreas. Tumors were verified and monitored by bioluminescence imaging (BLI) and mice randomized to treatment: STG (75mg/kg in drinking water), anti-PD-L1 Ab (200ug 3x/week), or both for 9 days. Controls received vehicle and/or isotype Ab. Tumors were harvested at endpoint and tumor infiltrating lymphocytes (TIL) and checkpoint expression was evaluated. Two in vivo studies evaluated survival (treated 3 weeks) or TIL (treated 9 days) for PDAC-bearing mice treated with STG, anti-PD-L1, and anti-Lag3 (including single, double, and triple therapy combinations). A combination study evaluating survival in mice orthotopically implanted with MT5 cells is ongoing.ResultsCD26 was among the most highly expressed genes in patient PDAC-derived CAFs vs. normal fibroblasts. CD26 protein was observed in human CAFs (HT137 and h-iPSC-PDAC-1) and PDAC cells (HPAC and PANC1) via immunoblot and flow, however, soluble CD26 was only observed in CAF supernatants (180 pg/mL and 587.6 pg/mL). Concurrent administration of STG and anti-PD-L1 Ab limited tumor progression and increased CD4, as well as increased CD8 (p’s