Decitibine improve the efficiency of anti-PD-1 therapy via activating the response to IFN/PD-L1 signal of lung cancer cells

Abstract

IFN-γ-induced PD-L1 expression represents the existence of tumor-specific T cells, which predicts high-response rate to anti-PD-1/L1 therapy, but loss-of-function of IFN signals (e.g., JAK mutation) induces adaptive immune resistance in patients with low-response rate. Interferon regulatory factors (IRF) are frequently epigenetic silenced in carcinogenesis, while the role of methylation in anti-PD-1/L1 therapy remains unclear. We here investigated the methylation status of IFN-γ related genes IRF1/8 and IFN-α/β-related genes IRF3/7 in lung cancer tissues and found that only highly methylated IRF1 and 7 negatively correlated to cd274 (coding PD-L1) expression, similar to JAK mutation. Interestingly, decitibine (DAC) as methylation inhibitor could hypomethylate IRF1/7 to restore PD-L1 level. Meanwhile, IRF7 enhanced constitutive PD-L1 expression, which was independent of IFN-γ though directly promote transcription of PD-L1, leading to abrogating cytotoxic T lymphocytes (CTLs) generation which could be restored by anti-PD-L1 antibody, or siRNA-IRF7. The supplement of DAC to anti-PD-1 therapy in vivo improve the efficiency of anti-tumor with less methylated IRF1/7, more interferon-related genes expression (e.g., CXCL9) and IFN-γ/CD8+ T-cells infiltrations, suggesting that additional treatment of DAC could rescue the ability to response to IFN in lung cancer patients with anti-PD-1/L1 therapy resistance.

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

“…In gastric cancer with high microsatellite instability (MSI-H), PD-L1 expression by immune cells is an important indicator of overall survival (OS) [15]. Decitabine improves the efficacy of anti-PD-1 therapy because PD-L1 in lung cancer cells is increased by IFN [16]. However, PD-L1 has the opposite effect when it exceeds a certain threshold; aromatic hydrocarbon receptor-induced PD-L1 overexpression in NSCLC reduces the efficacy of anti-PD-1 [17].…”

IRF1 Inhibits Antitumor Immunity through the Upregulation of PD-L1 in the Tumor Cell

“…IRF1 is an early-target gene downstream of IFNg signaling and modulates IFNg-mediated gene induction (19). IRF1 also regulates constitutive and inducible expression of PD-L1 by IFNg (20)(21)(22)(23). This led us to hypothesize that IRF1 might play a different role in tumor cells than in immune cells in determining the outcome of tumor progression.…”

The Protein Expression of PDL1 Is Highly Correlated with Those of eIF2α and ATF4 in Lung Cancer

“…The expression of IRF7 was negatively correlated with those of eIF2 α and ATF4 in the tumor tissue of SCC. IRF7 enhances the PDL1 expression by directly promoting its transcription [ 38 ]. However, the protein expression of PDL1 was negatively correlated with that of IRF7 in the tumor tissue of SCC.…”