Single Dual-specific Anti-PD-L1/TGF-β Antibody Synergizes with Chemotherapy as Neoadjuvant Treatment for Pancreatic Ductal Adenocarcinoma: a Preclinical Experimental Study

Abstract

Aims: Chemotherapy resistance is an important cause of neoadjuvant therapy failure in pancreatic ductal adenocarcinoma (PDAC). BiTP is a single antibody that can simultaneously and dually target transforming growth factor-beta (TGF-β) and programmed cell death 1 ligand 1 (PD-L1). We attempted in this study to investigate the efficacy of BiTP in combination with first-line chemotherapy in PDAC. Methods: Preclinical assessments of BiTP plus gemcitabine and nab-paclitaxel were completed through a resectable KPC mouse model (C57BL/6J). Spectral flow cytometry, tissue section staining, enzyme-linked immunosorbent assays, Counting Kit-8, transwell, and Western blot assays were used to investigate the synergistic effects. Results: BiTP combinatorial chemotherapy in neoadjuvant setting significantly downstaged PDAC tumors, enhanced survival and had a higher resectability for mice with PDAC. BiTP was high affinity binding to targets and reverse chemotherapy resistance of PDAC cells. The combination overcame immune evasion through reprogramming TME via increasing penetration and function of T cells, natural killer cells, and dendritic cells, and decreasing the function of immunosuppression-related cells as regulatory T cells, M2 macrophages, myeloid-derived suppressor cells, and cancer-associated fibroblasts. Conclusion: Our results suggest that the BiTP combinatorial chemotherapy is a promising neoadjuvant therapy for PDAC.