Effect and Mechanism of Interferon-Gamma Combined with Pembrolizumab on Chemoresistance of Lung Adenocarcinoma

Abstract

Tumor microenvironment can lead to chemotherapy resistance in lung cancer. PD-1 and PD-L1 are core regulatory molecules of immune checkpoint. Our study intends to assess IFN-γ combined with Pembrolizumab’s effect on chemoresistance of lung adenocarcinoma. Human A549/DDP lung adenocarcinoma resistant strains were cultured in vitro and randomly divided into control group, IFN-γ group and Pembrolizumab+IFN-γ group followed by analysis of cell proliferation by MTT assay, cell apoptosis by flow cytometry, the levels of PD-L1 and Bcl-2 by Western Blot, the level of interleukin-10 (IL-10) and IL-17 by ELISA, as well as the expression of JAK/STAT3 signaling pathway by Western Blot. IFN-γ-treated A549/DDP cells showed significantly inhibited cell apoptosis, promoted cell proliferation, increased level of IL-10, IL-17, and elevated expression of PD-L1 and Bcl-2, as well as increased phosphorylation of JAK and STAT3 (P < 0.05). However, Pembrolizumab combined with IFN-γ treatment significantly inhibited cell proliferation, increased cell apoptosis, decreased IL-10 and IL-17 level, PD-L1 and Bcl-2 expression as well as JAK and STAT3 phosphorylation with significant difference compared to IFN-γ treatment alone (P < 0.05). IFN-γ up-regulates PD-L1 expression by up-regulating the JAK/STAT3 pathway, inhibits the apoptosis of drug-resistant cells in lung adenocarcinoma, and promotes cell proliferation. Pembrolizumab can reverse IFN-γ’s effect on drug-resistant cells of lung adenocarcinoma, down-regulate JAK/STAT3 signaling pathway and, promote the apoptosis of drug-resistant lung cancer cells, and inhibit cell proliferation.