title: Regulation of PD-L1 expression on murine tumor-associated monocytes and macrophages by locally produced TNF-α.
abstract: PD-L1 is an immune checkpoint protein that has emerged as a major signaling molecule involved with tumor escape from T cell immune responses. Studies have shown that intra-tumoral expression of PD-L1 can inhibit antitumor immune responses. However, it has recently been shown that expression of PD-L1 on myeloid cells from the tumor is a stronger indicator of prognosis than tumor cell PD-L1 expression. Therefore, it is important to understand the factors that govern the regulation of PD-L1 expression on tumor-infiltrating myeloid cells. We found that immature bone marrow monocytes in tumor-bearing mice had low levels of PD-L1 expression, while higher levels of expression were observed on monocytes in circulation. In contrast, macrophages found in tumor tissues expressed much higher levels of PD-L1 than circulating monocytes, implying upregulation by the tumor microenvironment. We demonstrated that tumor-conditioned media strongly induced increased PD-L1 expression by bone marrow-derived monocytes and TNF-α to be a cytokine that causes an upregulation of PD-L1 expression by the monocytes. Furthermore, we found production of TNF-α by the monocytes themselves to be a TLR2-dependent response to versican secreted by tumor cells. Thus, PD-L1 expression by tumor macrophages appears to be regulated in a different manner than by tumor cells themselves.
authors.affiliation: From the Flint Animal Cancer Center, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Ft. Collins, CO, 80523, USA.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Hartley
authors.affiliation: From the Flint Animal Cancer Center, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Ft. Collins, CO, 80523, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Regan
authors.affiliation: From the Flint Animal Cancer Center, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Ft. Collins, CO, 80523, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Guth
authors.affiliation: From the Flint Animal Cancer Center, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Ft. Collins, CO, 80523, USA. sdow@colostate.edu.
authors.forename: Steven
authors.initials: S
authors.lastname: Dow
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000276:immunology*; D008545:Melanoma / Q000276:immunology*; D008546:Melanoma, Experimental; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology*; D009374:Neoplasms, Experimental; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D019139:Tumor Escape; D059016:Tumor Microenvironment; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D053675:Versicans / Q000378:metabolism
chemical_list: D060890:B7-H1 Antigen; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D053675:Versicans
keywords: Cytokine; Immune checkpoint; Myeloid; Tumor