Lentivirus-mediated RNA interference targeting programmed death receptor ligand 1 increases the immunologic anti-tumor effect of dendritic cell vaccination against pancreatic cancer in SCID-hu mice.

Abstract

Programmed death receptor ligand 1 (PD-L1), which belongs to the B7 family, is overexpressed in a variety of human cancer types and serves a crucial role in immune escape by malignant cells. Programmed death receptor 1 (PD-1) is a specific PD-L1 receptor. PD-1/PD-L1 signaling inhibits the antitumor effects of dendritic cell (DC) immunization for tumor treatment. The aim of the present study was to determine whether inhibiting PD-L1 may increase the immunologic anti-tumor effect of dendritic cells against pancreatic cancer. In the present study, PD-L1 levels in non-cancerous and malignant tissue samples were compared, and the impact of PD-L1 downregulation on human pancreatic cancer PaTu8988 cells was determined by lentivirus-based RNA interference and DC immunotherapy. PD-L1 expression in pancreatic specimens was assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry. PaTu8988 cells expressing reduced levels of PD-L1 were generated by lentivirus-based knockdown to assess the mechanism by which the inhibition of PD-L1 signaling in DC immunization affects therapeutic outcomes in pancreatic cancer-bearing SCID-hu mice. PD-L1 levels were markedly elevated in pancreatic adenocarcinoma samples compared with in non-cancerous tissue. PD-L1 silencing in pancreatic adenocarcinoma cells resulted in improved treatment outcomes of DC immunization in vitro and in vivo compared with traditional DC immunization. PD-L1 silencing enhances the antitumor response of cytotoxic T cells by increasing interferon γ production in vitro. In vivo, this method prevented tumor growth and lung metastasis, and prolonged survival in the SCID-hu model. In conclusion, the results of the present study suggested that suppressing PD-L1 in malignant cells during DC immunization may be a useful tool for immunotherapy in pancreatic adenocarcinoma.