Background: Interferon alpha (IFNα) is a well-established regulator of immunosuppression in head and neck squamous cell carcinoma (HNSCC), while the role of long noncoding RNAs (lncRNAs) in immunosuppression remains largely unknown. Methods: Differentially expressed lncRNAs were screened under IFNα stimulation using lncRNA sequencing. The role and mechanism of lncRNA in immunosuppression were investigated in HNSCC in vitro and in vivo. Results: We identified a novel IFNα-induced upregulated lncRNA, lncMX1–215, in HNSCC. LncMX1–215 was primarily located in the cell nucleus. Ectopic expression of lncMX1–215 markedly inhibited expression of the IFNα-induced, immunosuppression-related molecules programmed cell death 1 ligand 1 (PD-L1) and galectin-9, and vice versa. Subsequently, histone deacetylase (HDAC) inhibitors promoted the expression of PD-L1 and galectin-9. Binding sites for H3K27 acetylation were found on PD-L1 and galectin-9 promoters. Mechanistically, we found that lncMX1–215 directly interacted with GCN5, a known H3K27 acetylase, to interrupt its binding to H3K27 acetylation. Clinically, negative correlations between lncMX1–215 and PD-L1 and galectin-9 expression were observed. Finally, overexpression of lncMX1–215 suppressed HNSCC proliferation and metastasis capacity in vitro and in vivo. Conclusions: Our results suggest that lncMX1–215 negatively regulates immunosuppression by interrupting GCN5/H3K27ac binding in HNSCC, thus providing novel insights into immune checkpoint blockade treatment.

An 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. We 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. Overexpression 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. Our 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.

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