Interferon-alpha promotes immunosuppression through IFNAR1/STAT1 signalling in head and neck squamous cell carcinoma

Abstract

BackgroundAn immunosuppressive microenvironment is critical for cancer initiation and progression. Whether interferon alpha (IFNα) can suppress immune and cancer cells and its involved mechanism still remain largely elusive.MethodsWe examine the expression of interferon alpha/beta receptor-1 (IFNAR1), CD8, CD56 and programmed death ligand 1 (PDL1) in head and neck squamous cell carcinomas (HNSCC). The effect of IFNα on PDL1 and programmed cell death protein 1 (PD1) expression in tumour cells and immune cells was detected in vitro and in vivo.ResultsOverexpression of IFNAR1, MX1 and signal transducer and activator of transcription 1 (Stat1) indicated the endogenous IFNα activation in tumour microenvironment, which correlated with immunosuppression status in HNSCC patients. Moreover, IFNα transcriptionally activated the expression of PDL1 through p-Stat1 (Tyr701) and promoted PD1 expression in immune cells through IFNAR1. The inhibition of IFNα signalling enhanced the cytotoxic activity of nature killer cells. At lastastly, we confirmed the upregulation of PDL1 and PD1 in response to IFNα treatment in both xenograft tumour models and patient-derived xenograft models.ConclusionsOur findings demonstrate that IFNα-induced PDL1 and PD1 expression is a new mechanism of immunosuppression in HNSCC, suggesting that blocking IFNα signalling may enhance the efficacy of immune checkpoint blockade.

A novel IFNα-induced long noncoding RNA negatively regulates immunosuppression by interrupting H3K27 acetylation in head and neck squamous cell carcinoma

“…Last, we demonstrated that lncMX1-215 acts as a tumor suppressor during tumor progression. This study elucidates Several cells and cytokines have been reported to be involved in immunosuppression, such as tumor-associated macrophages [24], cancer-associated fibroblasts [25], myeloid-derived suppressor cells [26], regulatory T cells, TGF-β [27], IL-6 [28], and interferon [9]. Clarifying the regulatory networks involved in immunosuppression formation in the tumor microenvironment is critical and will contribute to clinical treatment with ICBs.…”

“…NK cell lysis assays were performed as previously described [9]. After being transfected for 24 h, HN4 and Cal27 cells were seeded in 96-well plates at 4~6 × 10 3 cells per well.…”

“…Our previous study demonstrated that endogenous interferon alpha (IFNα)-induced PD-L1 and PD-1 expression is a novel immunosuppression mechanism in HNSCC [9]. However, classic signal transducer and activator of transcription 1 (Stat1) signaling only plays a partial role in the immunosuppression mediated by IFNα.…”

Bioinformatics analysis and verification of molecular targets in ovarian cancer stem-like cells

“…Combinational treatment of IFN-α and IFN-γ inhibit growth and induces OC cells [ 59 ]. IFN-α signaling is mediated through a receptor complex of interferon-alpha/beta receptor-1 (IFNAR1) and IFNAR2, and these two subunits are significantly associated with an immunosuppressive environment in cancer [ 60 ]. IFITs are interferon's stimulated genes and identified as IFIT1, IFIT2, IFIT3, and IFIT5 in humans [ 61 , 62 ].…”

Type I interferons and endoplasmic reticulum stress in health and disease

“…1) (Ragimbeau et al, 2003;Uz e et al, 2007;Wallweber et al, 2014). In basal conditions the IFNAR1/2 cytoplasmic tails remain bound, in an inactive conformation, by the JAK proteins (Gui et al, 2017;Ma et al, 2019;Ragimbeau et al, 2003;Teijaro et al, 2016). Engagement by IFNα/β causes dimerization of IFNAR1/2 receptor chains thereby triggering the JAK/TYK2 kinase domains to undertake activation directed through their trans-phosphorylation (Pfeffer et al, 1997;Schneider et al, 2014).…”