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

• Published in: Nature (London) Vol. 545; no. 7655; pp. 495 - 499
• Main Authors: 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., Weissman, Irving L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.05.2017; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/31; 59/5; 631/250/251; 631/67/580; 64/60; 82/83; Animals; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Colonic Neoplasms - drug therapy; Colonic Neoplasms - immunology; Colonic Neoplasms - pathology; Disease Models, Animal; Female; Gene expression; Genetic aspects; Health aspects; Humanities and Social Sciences; Humans; letter; Macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Male; Mice; Mice, Inbred BALB C; multidisciplinary; Neoplasm Staging; Phagocytosis - drug effects; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - metabolism; Science; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature22396

Mouse and human tumour-associated macrophages express PD-1, which increases with cancer stage and induces decreased phagocytosis by macrophages; by contrast, PD-L1 removal increases phagocytosis in vivo , decreases tumour burden and increases survival of mice. Blocking tumour immunity Therapeutic antibodies that inhibit the interaction of programmed cell death protein (PD-1) with its ligand (PD-L1) are known to activate cytotoxic T cells. Here Irv Weissmann and colleagues study the role for PD-1 on tumour-infiltrating macrophages in mice. The study shows that PD-1-expressing macrophages have limited phagocytic capabilities and that blocking PD-1/PD-L1 enhances phagocytosis and correlates with reduced tumour growth. This finding suggests a T-cell-independent mechanism of therapeutic activity of PD-1/PD-L1 inhibitors which may be clinically relevant. 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 1 , 2 . Tumour cells frequently overexpress the ligand for PD-1, programmed cell death ligand 1 (PD-L1), facilitating their escape from the immune system 3 , 4 . 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 5 , 6 , 7 , 8 , 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 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.