Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

An intrinsic role of IL-33 in Treg cell–mediated tumor immunoevasion

Nature Immunology volume 21, pages 75–85 (2020)Cite this article

Subjects

Abstract

Regulatory T (Treg) cells accumulate into tumors, hindering the success of cancer immunotherapy. Yet, therapeutic targeting of Treg cells shows limited efficacy or leads to autoimmunity. The molecular mechanisms that guide Treg cell stability in tumors remain elusive. In the present study, we identify a cell-intrinsic role of the alarmin interleukin (IL)-33 in the functional stability of Treg cells. Specifically, IL-33-deficient Treg cells demonstrated attenuated suppressive properties in vivo and facilitated tumor regression in a suppression of tumorigenicity 2 receptor (ST2) (IL-33 receptor)-independent fashion. On activation, Il33−/− Treg cells exhibited epigenetic re-programming with increased chromatin accessibility of the Ifng locus, leading to elevated interferon (IFN)-γ production in a nuclear factor (NF)-κB–T-bet-dependent manner. IFN-γ was essential for Treg cell defective function because its ablation restored Il33−/− Treg cell-suppressive properties. Importantly, genetic ablation of Il33 potentiated the therapeutic effect of immunotherapy. Our findings reveal a new and therapeutically important intrinsic role of IL-33 in Treg cell stability in cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: IL-33 deficiency promotes anti-tumor immunity and inhibits tumor growth.
Fig. 2: Host-derived IL-33 role in tumor regression.
Fig. 3: Impaired suppressive function of IL-33-deficient Treg cells in vivo.
Fig. 4: IL-33-deficient Treg cells acquire a fragile phenotype.
Fig. 5: Role of IFN-γ in the impaired suppressive function of Il33−/− Treg cells.
Fig. 6: Increased NF-κB activation and T-bet expression promote IFN-γ production in Il33−/− Foxp3+ Treg cells.
Fig. 7: IL-33 deficiency potentiated immunotherapy efficacy.

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. The RNAseq and ATACseq data have been deposited in the Gene Expression Omnibus with the accession code GSE138874.

References

  1. Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Hatzioannou, A., Alissafi, T. & Verginis, P. Myeloid-derived suppressor cells and T regulatory cells in tumors: unraveling the dark side of the force. J. Leukoc. Biol. 102, 407–421 (2017).

    Article  Google Scholar 

  3. Zou, W. Regulatory T cells, tumour immunity and immunotherapy. Nat. Rev. Immunol. 6, 295–307 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Abdel-Wahab, N., Shah, M. & Suarez-Almazor, M. E. Adverse events associated with immune checkpoint blockade in patients with cancer: a systematic review of case reports. PLoS One 11, e0160221 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Jenkins, R. W., Barbie, D. A. & Flaherty, K. T. Mechanisms of resistance to immune checkpoint inhibitors. Br. J. Cancer 118, 9–16 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Liew, F. Y., Girard, J. P. & Turnquist, H. R. Interleukin-33 in health and disease. Nat. Rev. Immunol. 16, 676–689 (2016).

    Article  CAS  PubMed  Google Scholar 

  7. Cayrol, C. & Girard, J. P. Interleukin-33 (IL-33): a nuclear cytokine from the IL-1 family. Immunol. Rev. 281, 154–168 (2018).

    Article  CAS  PubMed  Google Scholar 

  8. Schiering, C. et al. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature 513, 564–568 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Overacre-Delgoffe, A. E. et al. Interferon-γ drives Treg fragility to promote anti-tumor immunity. Cell 169, 1130–1141.e11 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Overacre-Delgoffe, A. E. & Vignali, D. A. A. Treg fragility: a prerequisite for effective antitumor immunity? Cancer Immunol. Res. 6, 882–887 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Andersson, P. et al. Molecular mechanisms of IL-33-mediated stromal interactions in cancer metastasis. JCI Insight 3, e122375 (2018).

    Article  PubMed Central  Google Scholar 

  12. Setiady, Y. Y., Coccia, J. A. & Park, P. U. In vivo depletion of CD4 +FOXP3+ Treg cells by the PC61 anti-CD25 monoclonal antibody is mediated by FcγRIII + phagocytes. Eur. J. Immunol. 40, 780–786 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Braun, H., Afonina, I. S., Mueller, C. & Beyaert, R. Dichotomous function of IL-33 in health and disease: from biology to clinical implications. Biochem. Pharm. 148, 238–252 (2018).

    Article  CAS  PubMed  Google Scholar 

  14. Toker, A. et al. Active demethylation of the Foxp3 locus leads to the generation of stable regulatory T cells within the thymus. J. Immunol. 190, 3180–3188 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. Zeng, H. et al. mTORC1 couples immune signals and metabolic programming to establish Treg-cell function. Nature 499, 485–490 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Balasubramani, A. et al. Modular utilization of distal cis-regulatory elements controls Ifng gene expression in T cells activated by distinct stimuli. Immunity 33, 35–47 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ali, S. et al. The dual function cytokine IL-33 interacts with the transcription factor NF-κB to dampen NF-κB-stimulated gene transcription. J. Immunol. 187, 1609–1616 (2011).

    Article  CAS  PubMed  Google Scholar 

  18. Lin, L., Spoor, M. S., Gerth, A. J., Brody, S. L. & Peng, S. L. Modulation of Th1 activation and inflammation by the NF-κB repressor Foxj1. Science 303, 1017–1020 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Grinberg-Bleyer, Y. et al. NF-κB c-Rel Is crucial for the regulatory T cell immune checkpoint in cancer. Cell 170, 1096–1108 e1013 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hori, S. Lineage stability and phenotypic plasticity of Foxp3+ regulatory T cells. Immunol. Rev. 259, 159–172 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Apostolidis, S. A. et al. Phosphatase PP2A is requisite for the function of regulatory T cells. Nat. Immunol. 17, 556–564 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Huynh, A. et al. Control of PI3 kinase in Treg cells maintains homeostasis and lineage stability. Nat. Immunol. 16, 188–196 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Delgoffe, G. M. et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat. Immunol. 12, 295–303 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Shrestha, S. et al. Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat. Immunol. 16, 178–187 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wei, J. et al. Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis. Nat. Immunol. 17, 277–285 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yu, X. et al. Metabolic control of regulatory T cell stability and function by TRAF3IP3 at the lysosome. J. Exp. Med 215, 2463–2476 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. McClymont, S. A. et al. Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. J. Immunol. 186, 3918–3926 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Dominguez-Villar, M., Baecher-Allan, C. M. & Hafler, D. A. Identification of T helper type 1-like, Foxp3+ regulatory T cells in human autoimmune disease. Nat. Med. 17, 673–675 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Oldenhove, G. et al. Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 31, 772–786 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Di Pilato, M. et al. Targeting the CBM complex causes Treg cells to prime tumours for immune checkpoint therapy. Nature 570, 112–116 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Ouyang, W. et al. Novel Foxo1-dependent transcriptional programs control Treg cell function. Nature 491, 554–559 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lee, J. H., Elly, C., Park, Y. & Liu, Y. C. E3 ubiquitin ligase VHL regulates hypoxia-inducible factor-1α to maintain regulatory T cell stability and suppressive capacity. Immunity 42, 1062–1074 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Koch, M. A. et al. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat. Immunol. 10, 595–602 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Szabo, S. J. et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100, 655–669 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Levine, A. G. et al. Stability and function of regulatory T cells expressing the transcription factor T-bet. Nature 546, 421–425 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yu, F., Sharma, S., Edwards, J., Feigenbaum, L. & Zhu, J. Dynamic expression of transcription factors T-bet and GATA-3 by regulatory T cells maintains immunotolerance. Nat. Immunol. 16, 197–206 (2015).

    Article  CAS  PubMed  Google Scholar 

  37. Sekimata, M. et al. CCCTC-binding factor and the transcription factor T-bet orchestrate T helper 1 cell-specific structure and function at the interferon-γlocus. Immunity 31, 551–564 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhou, J., Fan, J. Y., Rangasamy, D. & Tremethick, D. J. The nucleosome surface regulates chromatin compaction and couples it with transcriptional repression. Nat. Struct. Mol. Biol. 14, 1070–1076 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Roussel, L., Erard, M., Cayrol, C. & Girard, J. P. Molecular mimicry between IL-33 and KSHV for attachment to chromatin through the H2A-H2B acidic pocket. EMBO Rep. 9, 1006–1012 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Carriere, V. et al. IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc. Natl Acad. Sci. USA 104, 282–287 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. Choi, Y. S. et al. Nuclear IL-33 is a transcriptional regulator of NF-κB p65 and induces endothelial cell activation. Biochem. Biophys. Res. Commun. 421, 305–311 (2012).

    Article  CAS  PubMed  Google Scholar 

  42. Travers, J. et al. Chromatin regulates IL-33 release and extracellular cytokine activity. Nat. Commun. 9, 3244 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Polesso, F., Sarker, M., Anderson, A., Parker, D. C. & Murray, S. E. Constitutive expression of NF-κB inducing kinase in regulatory T cells impairs suppressive function and promotes instability and pro-inflammatory cytokine production. Sci. Rep. 7, 14779 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Oh, H. et al. An NF-κB transcription-factor-dependent lineage-specific transcriptional program promotes regulatory T cell identity and function. Immunity 47, 450–465.e5 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kim, J. M., Rasmussen, J. P. & Rudensky, A. Y. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8, 191–197 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Alissafi, T., Hatzioannou, A., Legaki, A. I., Varveri, A. & Verginis, P. Balancing cancer immunotherapy and immune-related adverse events: the emerging role of regulatory T cells. J. Autoimmun. 104, 102310 (2019).

    Article  CAS  PubMed  Google Scholar 

  47. Liu, Z. et al. Modifying the cancer-immune set point using vaccinia virus expressing re-designed interleukin-2. Nat. Commun. 9, 4682 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Ishizuka, J. J. et al. Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Nature 565, 43–48 (2019).

    Article  CAS  PubMed  Google Scholar 

  49. Postow, M. A., Callahan, M. K. & Wolchok, J. D. Immune checkpoint blockade in cancer therapy. J. Clin. Oncol. 33, 1974–1982 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wei, S. C. et al. Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade. Cell 170, 1120–1133.e17 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Martin, P. et al. Disease severity in K/BxN serum transfer-induced arthritis is not affected by IL-33 deficiency. Arthritis Res. Ther. 15, R13 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hatzioannou, A. et al. Intratumoral accumulation of podoplanin-expressing lymph node stromal cells promote tumor growth through elimination of CD4+ tumor-infiltrating lymphocytes. Oncoimmunology 5, e1216289 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Gong, Y. et al. lncRNA-screen: an interactive platform for computationally screening long non-coding RNAs in large genomics datasets. BMC Genomics 18, 434 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).

    CAS  PubMed  Google Scholar 

  55. Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Buenrostro, J. D., Giresi, P. G., Zaba, L. C., Chang, H. Y. & Greenleaf, W. J. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat. Methods 10, 1213–1218 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with bowtie 2. Nat. Methods 9, 357–359 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Makridakis, M. & Vlahou, A. GeLC-MS: a sample preparation method for proteomics analysis of minimal amount of tissue. Methods Mol. Biol. 1788, 165–175 (2018).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank T. Alissafi for fruitful conversations and critical reading of the manuscript, R.M. Barouni for technical assistance, P. Alexakos for technical assistance on animal handling and maintenance and A. Apostolidou for technical assistance on flow cytometry and cell sorting. We also thank M. Makridakis and G. Kontostathi for PRM analysis. This work was supported by grants from the GGSRT (no. Aristeia II 3468 to P.V.). M.B. was funded by the German Research Foundation (grant no. BE 4427/3-1) and is a member of the excellence cluster ImmunoSensation. T.C. was supported by the ERC (grant no. DEMETINL-683145) and the German Research Foundation (grant no. SFB 1181, CO7). D.B. was supported by the ERC under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 742390). A.Hatzioannou is supported by IKY Fellowships of Excellence for Postgraduate Studies in Greece, Siemens Program and ‘Stratigos’ grant of the Hellenic Society of Melanoma Study. A.B. is financed by Greece and the European Union (European Social Fund) through the Operational Program ‘Human Resources Development, Education and Lifelong Learning’ in the context of the project ‘Reinforcement of Postdoctoral Researchers’ (no. MIS-5001552), implemented by the State Scholarships Foundation. D.B. and P.V. were supported by the European Union’s Horizon 2020 research and innovation program (grant agreement no. 733100).

Author information

Authors and Affiliations

  1. Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece

    Aikaterini Hatzioannou, Aggelos Banos, Dimitrios Boumpas & Panayotis Verginis

  2. Applied Bioinformatics Laboratories and Department of Pathology, New York University School of Medicine, New York, NY, USA

    Theodore Sakelaropoulos & Aristotelis Tsirigos

  3. Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA

    Theodore Sakelaropoulos

  4. Center of Basic Research, Biomedical Research Foundation Academy of Athens, Athens, Greece

    Constantinos Fedonidis

  5. Institute of Biology, Medicinal Chemistry & Biotechnology, National Hellenic Research Foundation, Athens, Greece

    Maria-Sophia Vidali & Panagiotis Georgiadis

  6. Molecular Immunology in Neurodegeneration, German Center for Neurodegenerative Diseases, Bonn, Germany

    Maren Köhne & Marc Beyer

  7. PRECISE, Platform for Single Cell Genomics and Epigenomics, German Center for Neurodegenerative Diseases and the University of Bonn, Bonn, Germany

    Kristian Händler & Marc Beyer

  8. Bioceros BV, Utrecht, the Netherlands

    Louis Boon

  9. Department of Immunology, Biomedical Sciences Research Centre ‘Alexander Fleming’, Vari, Greece

    Ana Henriques & Vasiliki Koliaraki

  10. Biotechnology Division, Biomedical Research Foundation of the Academy of Athens, Athens, Greece

    Jerome Zoidakis

  11. Department of Pesticides Control and Phytopharmacy, Benaki Phytopathological Institute, Athens, Greece

    Aikaterini Termentzi

  12. Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden, Germany

    Triantafyllos Chavakis & Panayotis Verginis

  13. National Center for Tumor Diseases, Partner Site Dresden and German Cancer Research Center, Heidelberg, Germany

    Triantafyllos Chavakis

  14. Joint Rheumatology Program, 4th Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece

    Dimitrios Boumpas

Authors
  1. Aikaterini Hatzioannou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aggelos Banos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Theodore Sakelaropoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Constantinos Fedonidis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maria-Sophia Vidali
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maren Köhne
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kristian Händler
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Louis Boon
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ana Henriques
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Vasiliki Koliaraki
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Panagiotis Georgiadis
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jerome Zoidakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Aikaterini Termentzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Marc Beyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Triantafyllos Chavakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Dimitrios Boumpas
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Aristotelis Tsirigos
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Panayotis Verginis
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.Hatzioannou and A.B. designed and performed experiments, analyzed the data, generated the figures and wrote the manuscript. C.F., M.-S.V., M.K., K.H. and A.Henriques performed experiments and analyzed the data. L.B. generated and provided critical reagents. T.S. and A.Tsirigos assisted with mRNA-seq and ATAC-seq data analysis and interpretation. T.S. generated the figures. J.Z. and A.Termentzi performed and analyzed the targeted proteomics experiments. V.K., P.G. and M.B. contributed to the data analysis and interpretation. T.C. and D.B. interpreted the data. P.V. designed and supervised the study, performed the data analysis and wrote the manuscript.

Corresponding author

Correspondence to Panayotis Verginis.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information L. A. Dempsey was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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

Supplementary information

Source data

Source Data Fig. 1

Statistical Source Data

Source Data Fig. 2

Statistical Source Data

Source Data Fig. 3

Statistical Source Data

Source Data Fig. 4

Statistical Source Data

Source Data Fig. 5

Statistical Source Data

Source Data Fig. 6

Statistical Source Data

Source Data Fig. 7

Statistical Source Data

Source Data Supplementary Fig. 1

Statistical Source Data

Source Data Supplementary Fig. 2

Statistical Source Data

Source Data Supplementary Fig. 3

Statistical Source Data

Source Data Supplementary Fig. 5

Statistical Source Data

Source Data Supplementary Fig. 6

Statistical Source Data

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hatzioannou, A., Banos, A., Sakelaropoulos, T. et al. An intrinsic role of IL-33 in Treg cell–mediated tumor immunoevasion. Nat Immunol 21, 75–85 (2020). https://doi.org/10.1038/s41590-019-0555-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41590-019-0555-2

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer