1. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity.
- Author
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Gordon, Sydney R, Maute, Roy L, Dulken, Ben W, Hutter, Gregor, George, Benson M, McCracken, Melissa N, Gupta, Rohit, Tsai, Jonathan M, Sinha, Rahul, Corey, Daniel, Ring, Aaron M, Connolly, Andrew J, and Weissman, Irving L
- Subjects
Cell Line ,Tumor ,Macrophages ,Animals ,Mice ,Inbred BALB C ,Humans ,Mice ,Colonic Neoplasms ,Disease Models ,Animal ,Neoplasm Staging ,Xenograft Model Antitumor Assays ,Cell Proliferation ,Phagocytosis ,Female ,Male ,Programmed Cell Death 1 Receptor ,B7-H1 Antigen ,General Science & Technology - Abstract
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.
- Published
- 2017