TY - JOUR
T1 - Interferon-alpha promotes immunosuppression through IFNAR1/STAT1 signalling in head and neck squamous cell carcinoma
AU - Ma, Hailong
AU - Yang, Wenyi
AU - Zhang, Liming
AU - Liu, Shuli
AU - Zhao, Mei
AU - Zhou, Ge
AU - Wang, Lizhen
AU - Jin, Shufang
AU - Zhang, Zhiyuan
AU - Hu, Jingzhou
N1 - Funding Information:
Funding: This study was supported by grants from the National Natural Science Foundation of China (Grant No. 81472516), the Natural Science Foundation of Shanghai (No. 14ZR1424200), China Postdoctoral Science Foundation (2018M632141) and the Shanghai Leading Academic Discipline Project (No. S30206).
Publisher Copyright:
© 2018, Cancer Research UK.
PY - 2019/2/5
Y1 - 2019/2/5
N2 - Background: 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. Methods: 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. Results: 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. Conclusions: 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.
AB - Background: 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. Methods: 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. Results: 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. Conclusions: 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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U2 - 10.1038/s41416-018-0352-y
DO - 10.1038/s41416-018-0352-y
M3 - Article
C2 - 30555157
AN - SCOPUS:85058671951
SN - 0007-0920
VL - 120
SP - 317
EP - 330
JO - British journal of cancer
JF - British journal of cancer
IS - 3
ER -