IFNAR1 Controls Autocrine Type I IFN Regulation of PD-L1 Expression in Myeloid-Derived Suppressor Cells

Abstract

Tumor cells respond to IFN-γ 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-α and IFN-β but not IFN-γ 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-α expression level nor IFN-β 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-γ from the suppressed T cells in the tumor microenvironment.

Evaluation of Newcastle disease virus mediated dendritic cell activation and cross‐priming tumor‐specific immune responses ex vivo

“…Furthermore, substantial upregulation of programmed cell death receptor ligand 1 (PD‐LI), an important immune checkpoint inhibitor of T cell activation, was observed. Previous studies have shown that type I IFN triggers PD‐LI expression on APCs . Indeed, significantly higher levels of cytokines such as IFN‐α and TNF‐α were detected in co‐culture with SKBR3_rNDV than with SKBR3 (Fig.…”

“…Previous studies have shown that type I IFN triggers PD-LI expression on APCs. 2,24 Indeed, significantly higher levels of cytokines such as IFN-α and TNF-α were detected in co-culture with SKBR3_rNDV than with SKBR3 ( Fig. 4b), no additional cytokine was detected as noted in the Table 1.…”

Basis of PD1/PD-L1 Therapies

“…The inhibition of the NF-κB pathway impairs the IFN-γ-mediated induction of PD-L1 expression [89], which is in line with the inhibition/downregulation of PD-L1 expression by inhibitors directed against NF-kB, JAK1/JAK2 and BTK [90]. In addition to IFN-γ, type I IFNs can also induce PD-L1 expression [91]. Other inflammatory stimuli affecting PD-L1 expression in tumors include lipopolysaccharide (LPS) by triggering TLR4, TNF-α and IL-4 and in DC, in particular IL-1β, IL-6, IL-27, IL-10 and TGF-β [13] (summarized by Sun et al, 2018).…”

Myeloid‐derived suppressor cells: Roles in the tumor microenvironment and tumor radiotherapy

“…If the process of the maturation of myeloid precursors was abrogated at different stages by some cytokines like TNF‐α, MDSCs will be generated eventually such pathological conditions as cancer (Fig. ) . The frequency of MDSCs was found to be closely associated with the progression and clinical staging in some cancer patients and tumor bearing mice.…”