Letter | Published:

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

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


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    , , , & Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11, 141–151 (1999)

  2. 2.

    et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027–1034 (2000)

  3. 3.

    & The PD-1–PD-L pathway in immunological tolerance. Trends Immunol. 27, 195–201 (2006)

  4. 4.

    , , & PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26, 677–704 (2008)

  5. 5.

    , & PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci. Transl. Med. 8, 328rv4 (2016)

  6. 6.

    The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012)

  7. 7.

    et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012)

  8. 8.

    et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369, 134–144 (2013)

  9. 9.

    et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 32, 1020–1030 (2014)

  10. 10.

    Tumour-educated macrophages promote tumour progression and metastasis. Nat. Rev. Cancer 4, 71–78 (2004)

  11. 11.

    et al. Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142, 699–713 (2010)

  12. 12.

    Forty Seven Inc. Phase 1 trial of Hu5F9-G4, a CD47-targeting antibody. (2014)

  13. 13.

    Phase 1, dose finding study of CC-90002 in subjects with advanced solid and hematologic cancers. (2015)

  14. 14.

    et al. PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc. Natl Acad. Sci. USA 106, 6303–6308 (2009)

  15. 15.

    et al. NF-κB regulates PD-1 expression in macrophages. J. Immunol. 194, 4545–4554 (2015)

  16. 16.

    , , , & Attenuation of the programmed cell death-1 pathway increases the M1 polarization of macrophages induced by zymosan. Cell Death Dis. 7, e2115 (2016)

  17. 17.

    et al. PD-1/PD-L pathway inhibits M.tb-specific CD4+ T-cell functions and phagocytosis of macrophages in active tuberculosis. Sci. Rep. 6, 38362 (2016)

  18. 18.

    , , & Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur. J. Cancer 42, 717–727 (2006)

  19. 19.

    , , , & Cutting edge: a possible role for CD4+ thymic macrophages as professional scavengers of apoptotic thymocytes. J. Immunol. 171, 2773–2777 (2003)

  20. 20.

    et al. CD4+/CD8+ macrophages infiltrating at inflammatory sites: a population of monocytes/macrophages with a cytotoxic phenotype. Blood 107, 2004–2012 (2006)

  21. 21.

    et al. CD4 ligation on human blood monocytes triggers macrophage differentiation and enhances HIV infection. J. Virol. 88, 9934–9946 (2014)

  22. 22.

    et al. Engineering high-affinity PD-1 variants for optimized immunotherapy and immuno-PET imaging. Proc. Natl Acad. Sci. USA 112, E6506–E6514 (2015)

  23. 23.

    et al. Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth. Cell 162, 1242–1256 (2015)

  24. 24.

    et al. The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors. Proc. Natl Acad. Sci. USA 105, 3011–3016 (2008)

  25. 25.

    et al. FcγRs modulate the anti-tumor activity of antibodies targeting the PD-1/PD-L1 axis. Cancer Cell 28, 285–295 (2015)

  26. 26.

    et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol. 8, 765–772 (1996)

  27. 27.

    et al. The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood 116, 2286–2294 (2010)

  28. 28.

    et al. PD-1 blunts the function of ovarian tumor-infiltrating dendritic cells by inactivating NF-κB. Cancer Res. 76, 239–250 (2016)

  29. 29.

    et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N. Engl. J. Med. 372, 311–319 (2015)

  30. 30.

    et al. Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed–Sternberg cells. Blood 125, 1061–1072 (2015)

  31. 31.

    et al. Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice. PLoS One 5, e13693 (2010)

  32. 32.

    et al. Genotyping the mouse severe combined immunodeficiency mutation using the polymerase chain reaction with confronting two-pair primers (PCR-CTPP). Exp. Anim. 51, 391–393 (2002)

  33. 33.

    et al. Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells. Nat. Immunol. 8, 1313–1323 (2007)

  34. 34.

    et al. An antibody against the colony-stimulating factor 1 receptor depletes the resident subset of monocytes and tissue- and tumor-associated macrophages but does not inhibit inflammation. Blood 116, 3955–3963 (2010)

Download references


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


  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


  1. Search for Sydney R. Gordon in:

  2. Search for Roy L. Maute in:

  3. Search for Ben W. Dulken in:

  4. Search for Gregor Hutter in:

  5. Search for Benson M. George in:

  6. Search for Melissa N. McCracken in:

  7. Search for Rohit Gupta in:

  8. Search for Jonathan M. Tsai in:

  9. Search for Rahul Sinha in:

  10. Search for Daniel Corey in:

  11. Search for Aaron M. Ring in:

  12. Search for Andrew J. Connolly in:

  13. Search for Irving L. Weissman in:


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.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains a Supplementary Figure and Supplementary Tables 1-3.

About this article

Publication history







By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.