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

By S. Gordon, R. Maute, Ben W. Dulken, G. Hutter, B. George, Melissa N. Mccracken, Rohit Gupta, Jonathan M. Tsai, Rahul Sinha, Daniel M. Corey and 3 more. Nature, 2017

1,957 citations recorded by the source corpus.

Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that is upregulated on activated T cells for the induction of immune tolerance. Tumour cells frequently overexpress the ligand for PD-1, programmed cell death ligand 1 (PD-L1), facilitating their escape from the immune system. Monoclonal antibodies that block the interaction between PD-1 and PD-L1, by binding to either the ligand or receptor, have shown notable clinical efficacy in patients with a variety of cancers, including melanoma, colorectal cancer, non-small-cell lung cancer and Hodgkin’s lymphoma. 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 in tumour-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 of cancer and with increasing disease stage in primary human cancers. TAM PD-1 expression correlates negatively with phagocytic potency against tumour cells, and blockade of PD-1–PD-L1 in vivo increases macrophage phagocytosis, reduces tumour growth and lengthens the survival of mice in mouse models of cancer in a macrophage-dependent fashion. This suggests that PD-1–PD-L1 therapies may also function through a direct effect on macrophages, with substantial implications for the treatment of cancer with these agents.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/b8fe47b60a0066448f2980cf462510a316346cf8

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Citations in the corpus

Mechanisms controlling PD-L1 expression in cancer (2019, background): “, 2016), and attenuating activation of immune cells, including TCR on T cells and the “don’t eat me” signaling on macrophages (Gordon et al., 2017; Zou et al., 2016).”
Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives (2021, background): “[139] observed increased expression of programmed cell death protein 1 (PD-1) on the cell surface of CAFinduced M2-type TAMs.”
Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab (2017, background): “Changes in macrophages on-therapy also associated with clinical response (Figure 4D), suggesting that macrophages may play an important role in response (Gordon et al., 2017).”
Organoid modeling of the tumor immune microenvironment (2018, background): “, 2011), or mediation of anti-PD-1 effects by TAMs (Gordon et al., 2017) and peripheral blood monocytes (Krieg et al.”
Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 (2018, neutral): “Somemyeloid cells have been proposed to express PD-1 (Gordon et al., 2017); however, both flow cytometry and scRNAseq analyses indicated that IL-12 DCs did not express the PD-1 receptor at both transcript (Figure S2A) and protein (Figure 3A) levels.”
The Tumor Microenvironment: A Milieu Hindering and Obstructing Antitumor Immune Responses (2020, background): “PD-1+ TAMs exhibit a declined phagocytosis due to the inhibitory role of PD-1 expression on TAMs compared to PD-1− TAMs (74).”
Tumor-associated macrophages: an accomplice in solid tumor progression (2019, background): “PD-L1 and PD-1 expression on TAMs can induce T cell exhaustion and potentially limit the efficacy of T cells associated immunotherapies in solid tumor [108].”
Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018, background): “Tumor-associated macrophages were also recently shown to express PD-1 in both mice and humans with colorectal cancer and to impair macrophage phagocytosis (59).”