Regulation of PD-L1 expression on murine tumor-associated monocytes and macrophages by locally produced TNF-[alpha]

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-[alpha] to be a cytokine that causes an upregulation of PD-L1 expression by the monocytes. Furthermore, we found production of TNF-[alpha] 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.