Letter | Published:

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

Nature volume 545, pages 495499 (25 May 2017) | Download Citation

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 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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Acknowledgements

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.

Author information

Affiliations

  1. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA

    • Sydney R. Gordon
    • , Roy L. Maute
    • , Ben W. Dulken
    • , Gregor Hutter
    • , Benson M. George
    • , Melissa N. McCracken
    • , Jonathan M. Tsai
    • , Rahul Sinha
    • , Daniel Corey
    •  & Irving L. Weissman
  2. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 4305, USA

    • Sydney R. Gordon
  3. Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA

    • Sydney R. Gordon
    • , Roy L. Maute
    • , Benson M. George
    • , Melissa N. McCracken
    • , Jonathan M. Tsai
    • , Rahul Sinha
    • , Daniel Corey
    •  & Irving L. Weissman
  4. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California 94305, USA

    • Sydney R. Gordon
    • , Roy L. Maute
    • , Benson M. George
    • , Melissa N. McCracken
    • , Jonathan M. Tsai
    • , Rahul Sinha
    • , Daniel Corey
    •  & Irving L. Weissman
  5. Department of Pathology, Stanford University Medical Center, Stanford, California 94305, USA

    • Sydney R. Gordon
    • , Roy L. Maute
    • , Benson M. George
    • , Melissa N. McCracken
    • , Jonathan M. Tsai
    • , Rahul Sinha
    • , Daniel Corey
    • , Andrew J. Connolly
    •  & Irving L. Weissman
  6. Stanford Medical Scientist Training Program, Stanford University, Stanford, California 94305, USA

    • Ben W. Dulken
    • , Benson M. George
    •  & Jonathan M. Tsai
  7. Department of Neurosurgery, Stanford University School of Medicine, Stanford, California 94305, USA.

    • Gregor Hutter
  8. Department of Neurosurgery, University Hospital Basel, CH-4031 Basel, Switzerland

    • Gregor Hutter
  9. Human Immune Monitoring Center Biobank, Stanford University School of Medicine, Palo Alto, California 94304, USA

    • Rohit Gupta
  10. Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519, USA

    • Aaron M. Ring

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Contributions

S.R.G. wrote the manuscript. S.R.G., R.L.M., M.N.M., A.M.R. and I.L.W. conceived and designed all experiments. S.R.G. performed TAM staining, made the HAC protein and conducted all in vivo studies, phagocytosis assays and analysis. B.W.D. and R.S. helped with FACS gating and TAM analysis. G.H. generated NSG Ccr2−/− mice. B.M.G. conducted bone marrow transplants. S.R.G., R.L.M. and M.N.M. generated cell lines. R.G. acquired human colon cancer samples. J.M.T. taught the immunofluorescence protocol. D.C. and A.J.C. characterized foamy TAMs. R.L.M. and I.L.W. supervised the research and edited the manuscript.

Competing interests

S.R.G., R.L.M., M.N.M., A.M.R. and I.L.W. are inventors on a patent (15/502,439) that is related to the HAC protein. S.R.G. and M.N.M. provide paid consulting services to Ab Initio Biotherapeutics Inc., which licensed this patent. R.L.M. and A.M.R. are founders of Ab Initio Biotherapeutics Inc.

Corresponding author

Correspondence to Irving L. Weissman.

Reviewer Information Nature thanks V. A. Boussiotis, M. De Palma and A. Mantovani for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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DOI

https://doi.org/10.1038/nature22396

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