PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis

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T cell non-Hodgkin lymphomas are a heterogeneous group of highly aggressive malignancies with poor clinical outcomes1. T cell lymphomas originate from peripheral T cells and are frequently characterized by genetic gain-of-function variants in T cell receptor (TCR) signalling molecules1,2,3,4. Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and cell survival programmes, it remains unclear whether T cells contain tumour suppressors that can counteract these events. Here we show that the acute enforcement of oncogenic TCR signalling in lymphocytes in a mouse model of human T cell lymphoma drives the strong expansion of these cells in vivo. However, this response is short-lived and robustly counteracted by cell-intrinsic mechanisms. A subsequent genome-wide in vivo screen using T cell-specific transposon mutagenesis identified PDCD1, which encodes the inhibitory receptor programmed death-1 (PD-1), as a master gene that suppresses oncogenic T cell signalling. Mono- and bi-allelic deletions of PDCD1 are also recurrently observed in human T cell lymphomas with frequencies that can exceed 30%, indicating high clinical relevance. Mechanistically, the activity of PD-1 enhances levels of the tumour suppressor PTEN and attenuates signalling by the kinases AKT and PKC in pre-malignant cells. By contrast, a homo- or heterozygous deletion of PD-1 allows unrestricted T cell growth after an oncogenic insult and leads to the rapid development of highly aggressive lymphomas in vivo that are readily transplantable to recipients. Thus, the inhibitory PD-1 receptor is a potent haploinsufficient tumour suppressor in T cell lymphomas that is frequently altered in human disease. These findings extend the known physiological functions of PD-1 beyond the prevention of immunopathology after antigen-induced T cell activation, and have implications for T cell lymphoma therapies and for current strategies that target PD-1 in the broader context of immuno-oncology.

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Change history

  • Corrected online 30 November 2017

    Please see accompanying Erratum (http://doi.org/10.1038/nature25142). Extended Data Fig. 5 of this Letter has been replaced, to remove the histology image that was obscuring panel a. The original figure is shown as Supplementary Information to the Erratum.


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  1. 1.

    et al. T-cell lymphoma: recent advances in characterization and new opportunities for treatment. J. Natl Cancer Inst. 109, djw248 (2016)

  2. 2.

    et al. Integrated molecular analysis of adult T cell leukemia/lymphoma. Nat. Genet. 47, 1304–1315 (2015)

  3. 3.

    et al. Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes. Nat. Genet. 47, 1426–1434 (2015)

  4. 4.

    et al. The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome. Nat. Genet. 47, 1465–1470 (2015)

  5. 5.

    et al. PLCG1 mutations in cutaneous T-cell lymphomas. Blood 123, 2034–2043 (2014)

  6. 6.

    et al. Genomic landscape of cutaneous T cell lymphoma. Nat. Genet. 47, 1011–1019 (2015)

  7. 7.

    , , , & Novel t(5;9)(q33;q22) fuses ITK to SYK in unspecified peripheral T-cell lymphoma. Leukemia 20, 313–318 (2006)

  8. 8.

    et al. The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma. J. Exp. Med. 207, 1031–1044 (2010)

  9. 9.

    Peripheral T cell lymphoma: new model + new insight. J. Exp. Med. 207, 911–913 (2010)

  10. 10.

    et al. TGF-β signalling is required for CD4+ T cell homeostasis but dispensable for regulatory T cell function. PLoS Biol. 11, e1001674 (2013)

  11. 11.

    et al. Role for E2F in control of both DNA replication and mitotic functions as revealed from DNA microarray analysis. Mol. Cell. Biol. 21, 4684–4699 (2001)

  12. 12.

    et al. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 1, 417–425 (2015)

  13. 13.

    et al. Identification of genes periodically expressed in the human cell cycle and their expression in tumors. Mol. Biol. Cell 13, 1977–2000 (2002)

  14. 14.

    et al. PiggyBac transposon mutagenesis: a tool for cancer gene discovery in mice. Science 330, 1104–1107 (2010)

  15. 15.

    et al. Genome-wide transposon screening and quantitative insertion site sequencing for cancer gene discovery in mice. Nat. Protocols 12, 289–309 (2017)

  16. 16.

    et al. A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer. Nat. Genet. 47, 47–56 (2015)

  17. 17.

    , , , & TAPDANCE: an automated tool to identify and annotate transposon insertion CISs and associations between CISs from next generation sequence data. BMC Bioinformatics 13, 154 (2012)

  18. 18.

    PD-1 signaling in primary T cells. Immunol. Rev. 229, 114–125 (2009)

  19. 19.

    , & The PD-1 pathway in tolerance and autoimmunity. Immunol. Rev. 236, 219–242 (2010)

  20. 20.

    , , , & PD-1 increases PTEN phosphatase activity while decreasing PTEN protein stability by inhibiting casein kinase 2. Mol. Cell. Biol. 33, 3091–3098 (2013)

  21. 21.

    , , , & SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J. Immunol. 173, 945–954 (2004)

  22. 22.

    et al. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3ζ signalosome and downstream signaling to PKCθ. FEBS Lett. 574, 37–41 (2004)

  23. 23.

    , & PD-1 regulates self-reactive CD8+ T cell responses to antigen in lymph nodes and tissues. J. Immunol. 179, 5064–5070 (2007)

  24. 24.

    et al. Site-specific recombination in human embryonic stem cells induced by cell-permeant Cre recombinase. Nat. Methods 3, 461–467 (2006)

  25. 25.

    et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012)

  26. 26.

    et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N. Engl. J. Med. 370, 1008–1018 (2014)

  27. 27.

    et al. PD-1 coinhibitory signals: the link between pathogenesis and protection. Semin. Immunol. 25, 219–227 (2013)

  28. 28.

    First use of CRISPR for gene therapy. Med. Sci. 32, 1035–1037 (2016)

  29. 29.

    et al. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity 15, 763–774 (2001)

  30. 30.

    , & HISAT: a fast spliced aligner with low memory requirements. Nat. Methods 12, 357–360 (2015)

  31. 31.

    et al. StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat. Biotechnol. 33, 290–295 (2015)

  32. 32.

    et al. Ballgown bridges the gap between transcriptome assembly and expression analysis. Nat. Biotechnol. 33, 243–246 (2015)

  33. 33.

    , , , & BubbleGUM: automatic extraction of phenotype molecular signatures and comprehensive visualization of multiple Gene Set Enrichment Analyses. BMC Genomics 16, 814 (2015)

  34. 34.

    et al. Memory of inflammation in regulatory T cells. Cell 166, 977–990 (2016)

  35. 35.

    , , , & Mammalian mutagenesis using a highly mobile somatic Sleeping Beauty transposon system. Nature 436, 221–226 (2005)

  36. 36.

    et al. Control-FREEC: a tool for assessing copy number and allelic content using next-generation sequencing data. Bioinformatics 28, 423–425 (2012)

  37. 37.

    , & GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics 14, 7 (2013)

  38. 38.

    et al. Hybrid HIV/MSCV LTR enhances transgene expression of lentiviral vectors in human CD34+ hematopoietic cells. Stem Cells 19, 236–246 (2001)

  39. 39.

    , , , & In vitro growth of cutaneous T-cell lymphomas. Cancer Treat. Rep. 63, 587–590 (1979)

  40. 40.

    et al. Bethesda proposals for classification of lymphoid neoplasms in mice. Blood 100, 246–258 (2002)

  41. 41.

    , & The utility of immunohistochemistry for the identification of hematopoietic and lymphoid cells in normal tissues and interpretation of proliferative and inflammatory lesions of mice and rats. Toxicol. Pathol. 40, 345–374 (2012)

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We thank N. Prause and K. Burmeister for providing technical assistance and S. Ogawa, K. Kataoka, R. P. Lifton and J. Choi for providing access to NGS data from patients with T cell lymphoma. This study used data generated by the Department of Pathology and Tumor Biology of Kyoto University. This work was supported by research grants from the DFG (SFB 1054/B01 and RU 695/6-1) and ERC (FP7, grant agreement no. 322865) awarded to J.R.

Author information


  1. Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany

    • Tim Wartewig
    • , Zsuzsanna Kurgyis
    • , Selina Keppler
    • , Konstanze Pechloff
    • , Erik Hameister
    • , Christof Winter
    •  & Jürgen Ruland
  2. TranslaTUM, Center for Translational Cancer Research, Technische Universität München, 81675 München, Germany

    • Tim Wartewig
    • , Zsuzsanna Kurgyis
    • , Selina Keppler
    • , Konstanze Pechloff
    • , Erik Hameister
    • , Rupert Öllinger
    • , Roman Maresch
    • , Christof Winter
    • , Roland Rad
    •  & Jürgen Ruland
  3. German Cancer Consortium (DKTK), 69120 Heidelberg, Germany

    • Konstanze Pechloff
    • , Christof Winter
    • , Roland Rad
    •  & Jürgen Ruland
  4. Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, 81675 München, Germany.

    • Rupert Öllinger
    • , Roman Maresch
    •  & Roland Rad
  5. Institute of Laboratory Animal Science, University of Zurich, Zurich, Switzerland

    • Thorsten Buch
  6. Institute of Pathology, Technische Universität München, 81675 München, Germany

    • Katja Steiger
  7. German Center for Infection Research (DZIF), partner site Munich, Germany.

    • Jürgen Ruland


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T.W. and J.R. designed the study. T.W. performed most of the experiments. Z.K. generated samples for RNA-seq experiments and the data for in vivo experiments with checkpoint inhibitors. S.K. performed intracellular flow cytometric and Phosflow analyses. K.P. contributed to in vivo experiments. E.H. performed experiments involving human cell lines and primary human cells. R.R. provided mouse lines and guidance for the transposon screen. R.Ö. and R.M. carried out the QiSeq and TAPDANCE analysis. K.S. performed the pathohistological analyses. C.W. performed the bioinformatical analysis on human WGS and WES data. T.W., K.P. and C.W. generated the figures. J.R., T.W. and C.W. wrote the manuscript. All authors discussed the results and contributed to the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jürgen Ruland.

Reviewer Information Nature thanks V. Boussiotis and the other anonymous reviewer(s) 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

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    Life Sciences Reporting Summary

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    This file contains Supplementary Tables 1-2.


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