PARP Inhibitor Upregulates PD-L1 Expression and Provides a New Combination Therapy in Pancreatic Cancer

Abstract

Despite recent improvements in treatment modalities, pancreatic cancer remains a highly lethal tumor with mortality rate increasing every year. Poly (ADP-ribose) polymerase (PARP) inhibitors are now used in pancreatic cancer as a breakthrough in targeted therapy. This study focused on whether PARP inhibitors (PARPis) can affect programmed death ligand-1 (PD-L1) expression in pancreatic cancer and whether immune checkpoint inhibitors of PD-L1/programmed death 1 (PD-1) can enhance the anti-tumor effects of PARPis. Here we found that PARPi, pamiparib, up-regulated PD-L1 expression on the surface of pancreatic cancer cells in vitro and in vivo. Mechanistically, pamiparib induced PD-L1 expression via JAK2/STAT3 pathway, at least partially, in pancreatic cancer. Importantly, pamiparib attenuated tumor growth; while co-administration of pamiparib with PD-L1 blockers significantly improved the therapeutic efficacy in vivo compared with monotherapy. Combination therapy resulted in an altered tumor immune microenvironment with a significant increase in windiness of CD8⁺ T cells, suggesting a potential role of CD8⁺ T cells in the combination therapy. Together, this study provides evidence for the clinical application of PARPis with anti-PD-L1/PD-1 drugs in the treatment of pancreatic cancer.

Keywords: CD8+ T cells; PARP inhibitors; PD-L1; pamiparib; pancreatic cancer.