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

Abstract

Tumor-associated macrophages (TAMs) express programmed cell death ligand 1 (PD-L1) and contribute to the immune-suppressive tumor microenvironment. Although the role of the PD-L1 and PD-1 interaction to regulate T-cell suppression is established, less is known about PD-L1 signaling in macrophages and how these signals may affect the function of TAMs. We used and models to investigate PD-L1 signaling in macrophages and the effects of PD-L1 antibody treatment on TAM responses. Treatment of mouse and human macrophages with PD-L1 antibodies increased spontaneous macrophage proliferation, survival, and activation (costimulatory molecule expression, cytokine production). Similar changes were observed in macrophages incubated with soluble CD80 and soluble PD-1, and in PD-L1 macrophages. Macrophage treatment with PD-L1 antibodies upregulated mTOR pathway activity, and RNAseq analysis revealed upregulation of multiple macrophage inflammatory pathways. treatment with PD-L1 antibody resulted in increased tumor infiltration with activated macrophages. In tumor-bearing RAG mice, upregulated costimulatory molecule expression by TAMs and reduced tumor growth were observed. Combined PD-1/ PD-L1 antibody treatment of animals with established B16 melanomas cured half of the treated mice, whereas treatment with single antibodies had little therapeutic effect. These findings indicate that PD-L1 delivers a constitutive negative signal to macrophages, resulting in an immune-suppressive cell phenotype. Treatment with PD-L1 antibodies reverses this phenotype and triggers macrophage-mediated antitumor activity, suggesting a distinct effect of PD-L1, but not PD-1, antibody treatment. .

Characterization of pulmonary immune responses to hyperoxia by high-dimensional mass cytometry analyses

“…However, we speculate that the upregulation of PD-L1 by macrophages may be an early adaptive response to counteract oxygen-induced alveolar inflammation. PD-L1 delivers an inhibitory signal to macrophages and other immune cells 38 , perhaps contributing to reduced proliferative rate of macrophages observed during hyperoxia by several authors 13,14 . In human ARDS, low expression of PD-L1 by alveolar macrophages is associated with prolonged mechanical ventilation and increased mortality 39 , indicating importance of PD-1/PD-L1 pathway in regulating the evolution of lung injury.…”

Cancer Stem Cell Target Labeling and Efficient Growth Inhibition of CD133 and PD-L1 Monoclonal Antibodies Double Conjugated with Luminescent Rare-Earth Tb3+ Nanorods

“…However, PD-L1 acts as an antiapoptotic receptor in response to Fas ligation. Therefore, PD-L1 is closely related to cancer stem cell proliferation [17]. PD-L1 antibodies are commercially available to clinically treat several types of cancer [18].…”

“…Herein, although TMC only slightly inhibited the growth of NTERA-2 cells in vitro, the nanocomplex strongly inhibited the growth of these 3D NTERA-2 spheroids when co-cultured with macrophages. According to Genevieve, PD-L1 monoclonal antibodies enhance the ability of macrophages to proliferate and activate, leading to increased numbers of TAM (tumor-associated macrophages) and thereby inhibiting the growth of tumor tissues [17].…”

Regulation of immune cell metabolism by cancer cell oncogenic mutations

“…The PD‐L1‐PD‐1 signaling axis suppresses macrophage glycolytic activity. Blocking PD‐1 promotes macrophage phagocytosis of malignant cells and activates the mTOR pathway in macrophages . Taken together, the current evidence indicates that immune checkpoint blockers reprogram immune cell metabolism to favor antitumor immune responses.…”