IFNAR1 controls autocrine type I IFN regulation of PD-L1 expression in myeloid-derived suppressor cells

Wei Xiao, John D. Klement, Chunwan Lu, Mohammed L. Ibrahim, Kebin Liu

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Tumor cells respond to IFN-g of activated T cells to upregulate programmed death-ligand 1 (PD-L1) in the tumor microenvironment as an adaptive immune resistance mechanism. Tumor cells also express oncogene-driven PD-L1. PD-L1 is also expressed on myeloid-derived suppressor cells (MDSCs). It is known that both type I and II IFNs upregulate PD-L1 expression in MDSCs. However, the molecular mechanism underlying PD-L1 expression in MDSCs is still largely unknown. We report in this article that MDSCs exhibit constitutive STAT1 phosphorylation in vitro without exogenous IFNs, indicating a constitutive active JAK-STAT signaling pathway in mouse MDSCs in vitro. Furthermore, IFN-a and IFN-b but not IFN-g are endogenously expressed in the MDSC cell line in vitro and in tumor-induced MDSCs in vivo. Neutralizing type I IFN or inhibiting the JAK-STAT signaling pathway significantly decreased constitutive PD-L1 expression in MDSCs in vitro. However, neither IFN-a expression level nor IFN-b expression level is correlated with PD-L1 expression level in MDSCs; instead, the level of IFN receptor type I (IFNAR1) is correlated with PD-L1 expression levels in MDSCs. Consequently, knocking out IFNAR1 in mice diminished PD-L1 expression in tumor-induced MDSCs. Therefore, we determined that 1) PD-L1 expression in MDSCs is activated by type I IFN through an autocrine manner and 2) the expression level of PD-L1 is controlled at least in part by the IFNAR1 level on MDSCs. Our data indicate that MDSCs may maintain their PD-L1 expression via autocrine type I IFN to exert their suppressive activity in the absence of IFN-g from the suppressed T cells in the tumor microenvironment.

Original languageEnglish (US)
Pages (from-to)264-277
Number of pages14
JournalJournal of Immunology
Volume201
Issue number1
DOIs
StatePublished - Jul 1 2018

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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