PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity

Abstract

Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that is upregulated on activated T cells to induce immune tolerance.1,2 Tumor cells frequently overexpress the ligand for PD-1, programmed cell death ligand 1 (PD-L1), facilitating escape from the immune system.3,4 Monoclonal antibodies blocking PD-1/PD-L1 have shown remarkable clinical efficacy in patients with a variety of cancers, including melanoma, colorectal cancer, non-small cell lung cancer, and Hodgkin’s lymphoma.5–9 Although it is well-established that PD-1/PD-L1 blockade activates T cells, little is known about the role that this pathway may have on tumor-associated macrophages (TAMs). Here we show that both mouse and human TAMs express PD-1. TAM PD-1 expression increases over time in mouse models, and with increasing disease stage in primary human cancers. TAM PD-1 expression negatively correlates with phagocytic potency against tumor cells, and blockade of PD-1/PD-L1 in vivo increases macrophage phagocytosis, reduces tumor growth, and lengthens survival in mouse models of cancer in a macrophage-dependent fashion. Our results suggest that PD-1/PD-L1 therapies may also function through a direct effect on macrophages, with significant implications for treatment with these agents.

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

“…Programmed cell death protein 1 (PD-1) is expressed by both lymphoid 2 and non-lymphoid immune cells, 3 , 4 and is up-regulated upon after engagement of T cell or B cell receptors on naïve lymphocytes. 2 , 4 Activation of PD-1 by its ligand PD-L1 induces down-regulation of lymphocyte proliferation and cytokine production, resulting in lymphocyte deletion.…”

Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells

“…Exchange of inhibitory Siglec-E with activating SigE16 (extracellular Siglec-E domain with transcellular activating human Siglec-16) showed T cell-dependent growth inhibition. In an adoptive transfer model, we demonstrated that Siglec-E on T cells is functionally involved, although the model we used, with OVA-specific OT-I T on myeloid cells and NK cells within the tumor (38,39). Further experiments are needed to understand the functional relevance of these immune-modulatory receptors, including Siglec-9 or PD-1, on cell types other than T cells.…”

SPON2 Promotes M1-like Macrophage Recruitment and Inhibits Hepatocellular Carcinoma Metastasis by Distinct Integrin–Rho GTPase–Hippo Pathways

“…Additionally, programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) may serve as a new regulatory 'checkpoint' for macrophages, given that macrophages express PD-1 in the tumour microenvironment (9). Because the C-C chemokine ligand 2 (CCL2) and colony-stimulating factor 1 (CSF-1) play critical roles in recruiting macrophages to neoplastic tissue, interest in therapeutics that target these Research. on May 12, 2018.…”