Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor that is upregulated on activated T cells for the induction of immune tolerance1,2. Tumour cells frequently overexpress the ligand for PD-1, programmed cell death ligand 1 (PD-L1), facilitating their escape from the immune system3,4. 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 lymphoma5,6,7,8,9. 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.
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The authors thank S. Karten for assistance in editing the manuscript; and A. McCarty, T. Storm and T. Naik for technical support. Research reported in this publication was supported by the D. K. Ludwig Fund for Cancer Research (to I.L.W.); the A.P. Giannini Foundation and the Stanford Dean’s Fellowship (to M.N.M.); the Stanford Medical Scientist Training Program NIH-GM07365 (to B.M.G., B.W.D. and J.M.T.); a Cancer Research Institute Irvington Fellowship (to R.L.M.); and a Swiss National Science Foundation fellowship P300P3_155336 (to G.H.). The project described was supported, in apart, by ARRA Award Number 1S10RR026780-01 from the National Center for Research Resources (NCRR). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCRR or the National Institutes of Health.
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Nature Reviews Gastroenterology & Hepatology (2019)