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Abstract

Most patients with colorectal cancer die as a result of the disease spreading to other organs. However, no prevalent mutations have been associated with metastatic colorectal cancers1,2. Instead, particular features of the tumour microenvironment, such as lack of T-cell infiltration3, low type 1 T-helper cell (TH1) activity and reduced immune cytotoxicity2 or increased TGFβ levels4 predict adverse outcomes in patients with colorectal cancer. Here we analyse the interplay between genetic alterations and the tumour microenvironment by crossing mice bearing conditional alleles of four main colorectal cancer mutations in intestinal stem cells. Quadruple-mutant mice developed metastatic intestinal tumours that display key hallmarks of human microsatellite-stable colorectal cancers, including low mutational burden5, T-cell exclusion3 and TGFβ-activated stroma4,6,7. Inhibition of the PD-1–PD-L1 immune checkpoint provoked a limited response in this model system. By contrast, inhibition of TGFβ unleashed a potent and enduring cytotoxic T-cell response against tumour cells that prevented metastasis. In mice with progressive liver metastatic disease, blockade of TGFβ signalling rendered tumours susceptible to anti-PD-1–PD-L1 therapy. Our data show that increased TGFβ in the tumour microenvironment represents a primary mechanism of immune evasion that promotes T-cell exclusion and blocks acquisition of the TH1-effector phenotype. Immunotherapies directed against TGFβ signalling may therefore have broad applications in treating patients with advanced colorectal cancer.

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Change history

  • 15 February 2018

    An incorrect present address was listed for Adrià Cañellas; this has now been corrected online.

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Acknowledgements

We thank E. Sancho for critical reading of this manuscript, all members of the Batlle laboratory for support and discussions, and members of the López-Bigas laboratory for help with revising the manuscript. We are grateful for the assistance of the IRB Barcelona core facilities for histopathology, functional genomics, mouse mutant and advanced digital microscopy; the flow cytometry and animal facilities of the UB/PCB; and the CRG genomic unit. D.V.F.T. held a Juan de la Cierva postdoctoral fellowship from MINECO. This work was supported by grants from the Doctor Josef Steiner Foundation, ERC advanced grant 340176, Instituto de Salud Carlos III, Olga Torres Foundation, BBVA Foundation, grant SAF-2014-53784 (MINECO) and by Fundación Botín. IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO.

Author information

Author notes

    • Alexandre Calon
    •  & Elisa I. Rivas

    Present address: Cancer Research Programme, Hospital del Mar Research Institute (IMIM), 08003 Barcelona, Spain (A.C. and E.I.R.).

Affiliations

  1. Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri i Reixac 10, 08028 Barcelona, Spain

    • Daniele V. F. Tauriello
    • , Sergio Palomo-Ponce
    • , Diana Stork
    • , Antonio Berenguer-Llergo
    • , Jordi Badia-Ramentol
    • , Marta Sevillano
    • , Sales Ibiza
    • , Adrià Cañellas
    • , Xavier Hernando-Momblona
    • , Daniel Byrom
    • , Joan A. Matarin
    • , Alexandre Calon
    • , Elisa I. Rivas
    • , Angel R. Nebreda
    • , Antoni Riera
    • , Camille Stephan-Otto Attolini
    •  & Eduard Batlle
  2. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain

    • Daniele V. F. Tauriello
    • , Sergio Palomo-Ponce
    • , Mar Iglesias
    • , Marta Sevillano
    • , Xavier Hernando-Momblona
    •  & Eduard Batlle
  3. Department of Pathology, Hospital del Mar, 08003 Barcelona, Spain

    • Mar Iglesias
  4. Cancer Research Programme, Hospital del Mar Research Institute (IMIM), 08003 Barcelona, Spain

    • Mar Iglesias
  5. Autonomous University of Barcelona (UAB), Spain

    • Mar Iglesias
  6. ICREA, Passeig Lluís Companys 23, 08010 Barcelona, Spain

    • Angel R. Nebreda
    •  & Eduard Batlle
  7. Department of Organic Chemistry, University of Barcelona, Martí i Franqués 1-11, 08028 Barcelona, Spain

    • Antoni Riera

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Contributions

D.V.F.T., S.P.-P., D.S. and A.Cal. performed animal husbandry and genotyping; M.S. performed immunohistochemistry; D.V.F.T. and M.I. analysed histopathology. D.V.F.T. generated MTOs, which D.V.F.T. and D.S. characterized in vitro; D.S. performed CRISPR experiments; C.S.-O.A. and A.B.-L. performed exome and RNA-seq analyses, other bioinformatics (CMS classifier and patient data), and statistical analyses. S.P.-P., D.V.F.T., J.B.-R., A.Cañ. and X.H.-M. performed mouse isografting; D.V.F.T., D.S. and J.B.-R. quantified immunohistochemistry. D.B., J.A.M. and A.R. synthesized galunisertib. D.V.F.T. coordinated and performed animal treatments and analysed the data. D.V.F.T., J.B.-R., S.I., E.I.R. and A.R.N. performed immunophenotyping experiments. E.B. and D.V.F.T. conceived the study, coordinated experiments and wrote the manuscript. E.B. supervised the study.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Eduard Batlle.

Reviewer Information Nature thanks L. Vermeulen 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.

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    This file contains the uncropped western blots, a Supplementary Discussion, Supplementary Acknowledgements, Supplementary Methods and Supplementary References

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https://doi.org/10.1038/nature25492

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