EBV up-regulates PD-L1 on the surface of primary monocytes by increasing ROS and activating TLR signaling and STAT3

Abstract

Programmed death ligand 1 (PD-L1) (also called B7-H1) is a membrane immune-modulatory protein whose overexpression on the surface of tumor cells as well as APCs impairs T-cell-mediated killing. Viruses that establish chronic infections have developed a number of strategies to escape from immune recognition including the up-regulation of PD-L1. This study shows for the first time that the human oncovirus EBV infects human primary monocytes using HLA-DR and induced a strong up-regulation of PD-L1 expression on their surface. Searching for the underlying mechanism/s leading to this immune suppressive effect, we found that EBV activated TLR signaling, increased intracellular ROS, and phosphorylated STAT3. Targeting these molecules partially reverted PD-L1 up-regulation that correlated with an altered cytokine production and a reduction of monocyte cell survival, strongly impairing the antiviral immune response.

Autophagy manipulation as a strategy for efficient anticancer therapies: possible consequences

“…stimulating the T regulatory cells (Treg) [35], altering class II antigen presentation or cross-presentation by DCs [36] or even impairing DC formation, all mechanisms inducing suppression of the immune response [37]. Interestingly, the reduction of autophagy in monocytes represents a strategy through which the human oncogenic gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) alter monocyte differentiation into DCs, to escape from immune recognition, as also demonstrated by our studies [38–40]. In line with the evidences indicating that autophagy is required for an effective immune response and for the activation of immune system in the course of anticancer chemotherapies, we have found that autophagy inhibitor CQ abrogates the cytotoxic effect of curcumin against breast cancer in immune competent mice while increases it in immune deficient mice [40].…”

Recent Findings in the Regulation of Programmed Death Ligand 1 Expression

“…TLR agonists-induced synthesis of PD-L1 has been observed in a variety of cell types (159–164). PAMPs from EBV was reported to induce PD-L1 upregulation in a TLR-dependent manner (136, 165, 166). Similarly, HIV stimulates PD-L1 expression on APC via TLR signaling or in an indirect manner by increasing the production of cytokines (149, 150).…”

The Tumor Microenvironment in Post-Transplant Lymphoproliferative Disorders

“…These chemokines in turn can attract Thelper type 2 and regulatory T-cells [57][58][59][60] which inhibit cytotoxic T cells. LMP1 and LMP2 have been shown to increase PD-L1 protein dosage through upregulation of an AP-1-dependent pathway and STAT3 signaling rather than chromosome 9p24.1 amplification, as is also observed in Hodgkin lymphoma and EBV+ PT-DLBCL [14,[32][33][34][35]. Surface expression of PD-L1 which inhibits cytotoxic T cell function through interaction with the PD1 receptor has been detected in about 90% of EBV-driven lymphomas including PTLD [61][62][63].…”