Macrophage PD-L1 strikes back: PD-1/PD-L1 interaction drives macrophages toward regulatory subsets

Abstract

<p> <span style="font-size:10pt;font-family:Verdana;">Activated macrophages have been simply de?ned as cells that secrete in?ammatory mediators and kill intracellular pathogens until few years ago. Recent studies have proposed a new classification system to separate activated macrophages based on their functional phenotypes: host defense, wound healing, and immune regulation. Regulatory macrophages can arise following innate or adaptive immune responses and hinder macrophage-mediated host defense and inflammatory functions by inhibiting the production of pro-inflammatory mediators. In this study, we investigated whether PD-1 and PD-L1 interaction between macrophages and T cells alters macrophage activities. Our data provide evidence for PD-1/PD-L1 engagement inducing a regulatory profile in macrophages. Regulatory macrophages derived from PD-L1 signaling lost their host defense activity, which consists of the production of pro-inflammatory cytokine IL-6 and the exhibition of increased IL-10, SPHK1 and LIGHT gene levels in early phases of LPS stimulation. This differentiation seems to occur through excessive activation of TLR4 downstream MAPK signaling pathways. Regulatory macrophages induced from PD-1/PD-L1 interaction decrease inflammatory mediators and produce anti-inflammatory cytokines, so this macrophage subset has been under considerable attention as a possible immune regulation mechanism. Understanding and modulating regulatory macrophages may lead to new approches to treat or prevent auto-immune diseases such as type I diabetes, rheumatic syndrome and hypersensitivity-related diseases, which are concerned with the overproduction of inflammatory cytokines in macroages. </span> </p

Programmed Cell Death Ligand 1 (PD-L1) Signaling Regulates Macrophage Proliferation and Activation

“…Thus, there is precedent for antitumor effects induced by PD-L1 antibody treatment that may not be related to T-cell PD-1 expression. Several reports have suggested additional roles for PD-L1 in regulating tumor cell and dendritic cell activity (6)(7)(8)(9)(10)(11)(12)(13)(14), but little is known concerning the role of PD-L1 in regulating macrophage function.…”

“…Increased ERK-and mTOR-mediated proliferation and survival of tumor cells has been reported following ligation of PD-L1 with PD-1 or when in culture with PD-1-expressing T cells (11,12). Ligation of PD-L1 on dendritic cells using soluble PD-1 downregulated maturation-associated markers and a murine macrophage cell line showed greater immune-suppressive phenotype following PD-L1 antibody treatment (13,14). Little is known, however, regarding PD-L1 signaling in macrophages, especially tumor-associated macrophages (TAMs).…”

Dynamic Changes in PD-L1 Expression and Immune Infiltrates Early During Treatment Predict Response to PD-1 Blockade in Melanoma

“…The presence of PD-1 þ T cells within or surrounding tumors indicates a population of T cells that have been stimulated by tumor-specific antigens (4,(15)(16)(17)(18). These activated and terminally differentiated cytotoxic T cells are susceptible to be induced into a state of anergy by the binding of their PD-1 receptor by PD-L1-expressing tumor or other PD-L1-expressing antigen-presenting cells (APC), such as macrophages and dendritic cells (19). The abundance of intratumoral and peritumoral PD-1 þ T cells in the PRE biopsies of responders (but not in nonresponders) is consistent with the notion that their presence, in conjunction with tumor and macrophage PD-L1 expression, indicates a degree of PD-L1-mediated T-cell inactivation, which upon being disinhibited by humanized anti-PD-1 mAbs, reactivates the tumoricidal function of these tumor-specific cytotoxic T cells.…”

“…Macrophages can stimulate antigen-specific T cells via T-cell receptor/MHC signaling in their role as APCs (23). Conversely, APCs can also induce T-cell anergy via activating PD-1 receptors by their PD-L1 ligand (19), and indeed, "immune cell" PD-L1 expression, rather than tumor PD-L1 expression, has been previously shown to correlate with anti-PD-1 therapy response (24). Furthermore, macrophages can also be stimulated to adopt a regulatory function as the result of PD-L1/PD-1 engagement, resulting in the reduced production of proinflammatory cytokines (IL6) and enhanced secretion of antiinflammatory cytokines (IL10; ref.…”

“…Furthermore, macrophages can also be stimulated to adopt a regulatory function as the result of PD-L1/PD-1 engagement, resulting in the reduced production of proinflammatory cytokines (IL6) and enhanced secretion of antiinflammatory cytokines (IL10; ref. 19), thereby contributing to immunosuppression (25). The disengagement of T-cell PD-1 from macrophage PD-L1, mediated by anti-PD-1 antibodies, may not just re-activate cytotoxic PD-1 þ T cells but also promote regulatory macrophages to adopt a more proinflammatory state and secrete a range of inflammatory cytokines enhancing the influx of activated T cells.…”