title: The expression profiles and regulation of PD-L1 in tumor-induced myeloid-derived suppressor cells.
abstract: Programmed death-ligand 1 (PD-L1) is an inhibitory ligand that binds to PD-1 to suppress T cell activation. PD-L1 is constitutively expressed and inducible in tumor cells, but the expression profiles and regulatory mechanism of PD-L1 in myeloid-derived suppressor cells (MDSCs) are largely unknown. We report that PD-L1 is abundantly expressed in tumor-infiltrating leukocytes in human patients with both microsatellite instable and microsatellite stable colon cancer. About 60% CD11b+CD33+HLA-DR-MDSCs from peripheral blood of human colon cancer patients are PD-L1+. PD-L1+MDSCs are also significantly higher in tumor-bearing mice than in tumor-free mice. Interestingly, the highest PD-L1+MDSCs were observed in the tumor microenvironment in which 56-71% tumor-infiltrating MDSCs are PD-L1+in vivo. In contrast, PD-L1+MDSCs are significantly less in secondary lymphoid organs and peripheral blood as compared to the tumor tissues, whereas bone marrow MDSCs are essentially PD-L1-in tumor-bearing mice. IFNγ is highly expressed in cells of the tumor tissues and IFNγ neutralization significantly decreased PD-L1+MDSCs in the tumor microenvironmentin vivo. However, IFNγ-activated pSTAT1 does not bind to thecd274promoter in MDSCs. Instead, pSTAT1 activates expression of IRF1, IRF5, IRF7 and IRF8 in MDSCs, and only pSTAT1-activated IRF1 binds to a unique IRF-binding sequence elementin vitroand chromatinin vivoin thecd274promoter to activate PD-L1 transcription. Our data determine that PD-L1 is highly expressed in tumor-infiltrating MDSCs and in a lesser degree in lymphoid organs, and the pSTAT1-IRF1 axis regulates PD-L1 expression in MDSCs.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Chunwan
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA; Georgia Cancer Center, Augusta University, Augusta, GA, USA.
authors.forename: Priscilla S
authors.initials: PS
authors.lastname: Redd
authors.affiliation: Charlie Norwood VA Medical Center, Augusta, GA, USA; Pathology, Medical College of Georgia, Augusta, GA, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Lee
authors.affiliation: Pathology, Medical College of Georgia , Augusta, GA, USA.
authors.forename: Natasha
authors.initials: N
authors.lastname: Savage
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, USA; Charlie Norwood VA Medical Center, Augusta, GA, USA; Georgia Cancer Center, Augusta University, Augusta, GA, USA.
authors.forename: Kebin
authors.initials: K
authors.lastname: Liu
keywords: IFNγ; MDSCs; MSI colon cancer; MSS colon cancer; PD-L1; T cells