TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis

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-h...

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Autores: Tauriello, Daniele V. F., Palomo Ponce, Sergio, Stork, Diana, Berenguer Llergo, Antoni, Badia Ramentol, Jordi, Iglesias, Mar, Sevillano, Marta, Ibiza, Sales, Cañellas, Adrià, Hernando Momblona, Xavier, Byrom, Daniel, Matarin, Joan A., Calon, Alexandre, Rivas, Elisa I., Nebreda, Àngel R., Riera Mestre, Antoni, Otto Attolini, Camille Stephan, Batlle, Eduard
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2018
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/120345
Acceso en línea:https://hdl.handle.net/2445/120345
Access Level:acceso abierto
Palabra clave:Càncer colorectal
Metàstasi
Colorectal cancer
Metastasis
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spelling TGFβ drives immune evasion in genetically reconstituted colon cancer metastasisTauriello, Daniele V. F.Palomo Ponce, SergioStork, DianaBerenguer Llergo, AntoniBadia Ramentol, JordiIglesias, MarSevillano, MartaIbiza, SalesCañellas, AdriàHernando Momblona, XavierByrom, DanielMatarin, Joan A.Calon, AlexandreRivas, Elisa I.Nebreda, Àngel R.Riera Mestre, AntoniOtto Attolini, Camille StephanBatlle, EduardCàncer colorectalMetàstasiColorectal cancerMetastasisMost 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.2018info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2445/120345Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésVersió postprimt del document publicat a: http://dx.doi.org/10.1038/nature25492Nature, 2018, num. 554http://dx.doi.org/10.1038/nature25492(c) Nature Publishing Group, 2018info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1203452026-05-27T06:46:51Z
dc.title.none.fl_str_mv TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis
title TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis
spellingShingle TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis
Tauriello, Daniele V. F.
Càncer colorectal
Metàstasi
Colorectal cancer
Metastasis
title_short TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis
title_full TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis
title_fullStr TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis
title_full_unstemmed TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis
title_sort TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis
dc.creator.none.fl_str_mv Tauriello, Daniele V. F.
Palomo Ponce, Sergio
Stork, Diana
Berenguer Llergo, Antoni
Badia Ramentol, Jordi
Iglesias, Mar
Sevillano, Marta
Ibiza, Sales
Cañellas, Adrià
Hernando Momblona, Xavier
Byrom, Daniel
Matarin, Joan A.
Calon, Alexandre
Rivas, Elisa I.
Nebreda, Àngel R.
Riera Mestre, Antoni
Otto Attolini, Camille Stephan
Batlle, Eduard
author Tauriello, Daniele V. F.
author_facet Tauriello, Daniele V. F.
Palomo Ponce, Sergio
Stork, Diana
Berenguer Llergo, Antoni
Badia Ramentol, Jordi
Iglesias, Mar
Sevillano, Marta
Ibiza, Sales
Cañellas, Adrià
Hernando Momblona, Xavier
Byrom, Daniel
Matarin, Joan A.
Calon, Alexandre
Rivas, Elisa I.
Nebreda, Àngel R.
Riera Mestre, Antoni
Otto Attolini, Camille Stephan
Batlle, Eduard
author_role author
author2 Palomo Ponce, Sergio
Stork, Diana
Berenguer Llergo, Antoni
Badia Ramentol, Jordi
Iglesias, Mar
Sevillano, Marta
Ibiza, Sales
Cañellas, Adrià
Hernando Momblona, Xavier
Byrom, Daniel
Matarin, Joan A.
Calon, Alexandre
Rivas, Elisa I.
Nebreda, Àngel R.
Riera Mestre, Antoni
Otto Attolini, Camille Stephan
Batlle, Eduard
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Càncer colorectal
Metàstasi
Colorectal cancer
Metastasis
topic Càncer colorectal
Metàstasi
Colorectal cancer
Metastasis
description 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.
publishDate 2018
dc.date.none.fl_str_mv 2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/120345
url https://hdl.handle.net/2445/120345
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprimt del document publicat a: http://dx.doi.org/10.1038/nature25492
Nature, 2018, num. 554
http://dx.doi.org/10.1038/nature25492
dc.rights.none.fl_str_mv (c) Nature Publishing Group, 2018
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Nature Publishing Group, 2018
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300724

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