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.

Viruses as tools in gene therapy, vaccine development, and cancer treatment

“…In vitro and in vivo lentivirus-based RNA silencing of PD-L1 signaling in a pancreatic cancer cell line and in SCID-hu mice with pancreatic cancer showed improved results after dendritic cell (DC) immunization. An in vitro investigation showed a cytotoxic T-cell-based antitumor response, while in vivo , lung metastasis and tumor growth in mice were inhibited and survival rates increased [ 164 ]. In one study, an integrase-defective lentiviral vector (IDLV) was engineered to express genes for the influenza virus nucleoprotein (NP) and hemagglutinin (HA), and this was used to inoculate CB6F1 mice.…”

RNA Interference and Nanotechnology: A Promising Alliance for Next Generation Cancer Therapeutics

“…The antitumor effects of dendritic cell (DC) immunization have been observed to be inhibited by the signaling functions of PD-1/PD-L1. The shutdown of the PD-L1 expression by lentivirus-mediated RNAi in SCID-hu mice injected with human pancreatic cancer PaTu8988 cells (Wang et al, 2019), reduced the tumor growth and lung metastasis thereby increasing the survival time of SCIDhu mice. Staphylococcal nuclease domain-containing protein 1 (SND1), also termed as P100 is a major component of RISC complex which regulates gene expression at both transcriptional and translational levels.…”

Novel therapeutic strategies and perspectives for metastatic pancreatic cancer: vaccine therapy is more than just a theory

“…Preclinical data indicated that DC vaccines combined with ICBs could generate a synergistic effect with low additional toxicity [40]. Moreover, PD-L1 knockdown by lentivirus-mediated RNA interference combined with DC vaccination may enhance T cell activity in PC on inhibiting metastasis and improving survival [41]. Furthermore, the cancer vaccine GVAX combined with anti PD-1/PD-L1 therapy increased CD8+ T infiltration into pancreatic tumors and improved patient survival [42].…”