Journal ArticleDOI
Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity
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TLDR
The mechanism by which tumour-intrinsic active β-catenin signalling results in T-cell exclusion and resistance to anti-PD-L1/anti-CTLA-4 monoclonal antibody therapy is identified, pointing to new candidate targets for immune potentiation.Abstract:
Melanoma treatment is being revolutionized by the development of effective immunotherapeutic approaches. These strategies include blockade of immune-inhibitory receptors on activated T cells; for example, using monoclonal antibodies against CTLA-4, PD-1, and PD-L1 (refs 3-5). However, only a subset of patients responds to these treatments, and data suggest that therapeutic benefit is preferentially achieved in patients with a pre-existing T-cell response against their tumour, as evidenced by a baseline CD8(+) T-cell infiltration within the tumour microenvironment. Understanding the molecular mechanisms that underlie the presence or absence of a spontaneous anti-tumour T-cell response in subsets of cases, therefore, should enable the development of therapeutic solutions for patients lacking a T-cell infiltrate. Here we identify a melanoma-cell-intrinsic oncogenic pathway that contributes to a lack of T-cell infiltration in melanoma. Molecular analysis of human metastatic melanoma samples revealed a correlation between activation of the WNT/β-catenin signalling pathway and absence of a T-cell gene expression signature. Using autochthonous mouse melanoma models we identified the mechanism by which tumour-intrinsic active β-catenin signalling results in T-cell exclusion and resistance to anti-PD-L1/anti-CTLA-4 monoclonal antibody therapy. Specific oncogenic signals, therefore, can mediate cancer immune evasion and resistance to immunotherapies, pointing to new candidate targets for immune potentiation.read more
Citations
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Journal ArticleDOI
Cancer immunotherapy using checkpoint blockade
TL;DR: New-generation combinatorial therapies may overcome resistance mechanisms to immune checkpoint therapy, and evidence points to alterations that converge on the antigen presentation and interferon-γ signaling pathways.
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Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors
Bertrand Routy,Bertrand Routy,Bertrand Routy,Lisa Derosa,Lisa Derosa,Lisa Derosa,Connie P.M. Duong,Connie P.M. Duong,Maryam Tidjani Alou,Maryam Tidjani Alou,Maryam Tidjani Alou,Romain Daillère,Romain Daillère,Romain Daillère,Aurélie Fluckiger,Aurélie Fluckiger,Meriem Messaoudene,Meriem Messaoudene,Conrad Rauber,Conrad Rauber,Conrad Rauber,Maria Paula Roberti,Maria Paula Roberti,Marine Fidelle,Marine Fidelle,Caroline Flament,Caroline Flament,Vichnou Poirier-Colame,Vichnou Poirier-Colame,Paule Opolon,Christophe Klein,Kristina Iribarren,Laura Mondragón,Nicolas Jacquelot,Nicolas Jacquelot,Nicolas Jacquelot,Bo Qu,Bo Qu,Bo Qu,Gladys Ferrere,Gladys Ferrere,Gladys Ferrere,Céline Clémenson,Céline Clémenson,Laura Mezquita,Jordi Remon Masip,C. Naltet,Solenn Brosseau,Coureche Kaderbhai,Corentin Richard,Hira Rizvi,Florence Levenez,Nathalie Galleron,Benoit Quinquis,Nicolas Pons,Bernhard Ryffel,Veronique Minard-Colin,Patrick Gonin,Jean-Charles Soria,Eric Deutsch,Eric Deutsch,Yohann Loriot,Yohann Loriot,François Ghiringhelli,Gérard Zalcman,François Goldwasser,B. Escudier,B. Escudier,Matthew D. Hellmann,Matthew D. Hellmann,Alexander M.M. Eggermont,Alexander M.M. Eggermont,Didier Raoult,Laurence Albiges,Laurence Albiges,Guido Kroemer,Laurence Zitvogel +76 more
TL;DR: It is found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition, and Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer.
Journal ArticleDOI
Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy.
TL;DR: As the molecular mechanisms of resistance to immunotherapy are elucidated, actionable strategies to prevent or treat them may be derived to improve clinical outcomes for patients.
Journal ArticleDOI
Understanding the tumor immune microenvironment (TIME) for effective therapy.
Mikhail Binnewies,Edward W. Roberts,Kelly Kersten,Vincent Chan,Douglas F. Fearon,Miriam Merad,Lisa M. Coussens,Dmitry I. Gabrilovich,Suzanne Ostrand-Rosenberg,Suzanne Ostrand-Rosenberg,Catherine C. Hedrick,Robert H. Vonderheide,Mikael J. Pittet,Rakesh K. Jain,Weiping Zou,T. Kevin Howcroft,Elisa C. Woodhouse,Robert A. Weinberg,Matthew F. Krummel +18 more
TL;DR: By parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient’s tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.
Journal ArticleDOI
TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.
Sanjeev Mariathasan,Shannon J. Turley,Dorothee Nickles,Alessandra Castiglioni,Kobe C. Yuen,Yulei Wang,Edward E. Kadel,Hartmut Koeppen,Jillian L. Astarita,Rafael Cubas,Suchit Jhunjhunwala,Romain Banchereau,Yagai Yang,Yinghui Guan,Cecile Chalouni,James Ziai,Yasin Senbabaoglu,Stephen Santoro,Daniel Sheinson,Jeffrey Hung,Jennifer M. Giltnane,Andrew A. Pierce,Kathryn Mesh,Steve Lianoglou,Johannes Riegler,Richard A.D. Carano,Pontus Eriksson,Mattias Höglund,Loan Somarriba,Daniel L. Halligan,Michiel S. van der Heijden,Yohann Loriot,Jonathan E. Rosenberg,Lawrence Fong,Ira Mellman,Daniel S. Chen,Marjorie C. Green,Christina Louise Derleth,Gregg Fine,Priti S. Hegde,Richard Bourgon,Thomas Powles +41 more
TL;DR: Tumours from a large cohort of patients with metastatic urothelial cancer who were treated with an anti-PD-L1 agent were examined and major determinants of clinical outcome were identified and suggested that TGFβ shapes the tumour microenvironment to restrain anti-tumour immunity by restricting T-cell infiltration.
References
More filters
Journal ArticleDOI
Analyzing real-time PCR data by the comparative C(T) method.
TL;DR: This protocol provides an overview of the comparative CT method for quantitative gene expression studies and various examples to present quantitative gene Expression data using this method.
Journal ArticleDOI
RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome
Bo Li,Colin N. Dewey +1 more
TL;DR: It is shown that accurate gene-level abundance estimates are best obtained with large numbers of short single-end reads, and estimates of the relative frequencies of isoforms within single genes may be improved through the use of paired- end reads, depending on the number of possible splice forms for each gene.
Journal ArticleDOI
Improved Survival with Ipilimumab in Patients with Metastatic Melanoma.
F. Stephen Hodi,Steven J. O'Day,David F. McDermott,R. W. Weber,Jeffrey A. Sosman,John B. A. G. Haanen,Rene Gonzalez,Caroline Robert,Dirk Schadendorf,Jessica C. Hassel,Wallace Akerley,Alfons J.M. van den Eertwegh,Jose Lutzky,Paul Lorigan,Julia Vaubel,Gerald P. Linette,David W. Hogg,Christian H. Ottensmeier,Céleste Lebbé,Christian Peschel,Ian Quirt,Joseph I. Clark,Jedd D. Wolchok,Jeffrey S. Weber,Jason Tian,Michael Yellin,Geoffrey M. Nichol,Axel Hoos,Walter J. Urba +28 more
TL;DR: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma.
Journal ArticleDOI
ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data
TL;DR: The ANNOVAR tool to annotate single nucleotide variants and insertions/deletions, such as examining their functional consequence on genes, inferring cytogenetic bands, reporting functional importance scores, finding variants in conserved regions, or identifying variants reported in the 1000 Genomes Project and dbSNP is developed.
Journal ArticleDOI
An integrated map of genetic variation from 1,092 human genomes
Gonçalo R. Abecasis,Adam Auton,Lisa D. Brooks,Mark A. DePristo,Richard Durbin,Robert E. Handsaker,Robert E. Handsaker,Hyun Min Kang,Gabor T. Marth,Gil McVean +9 more
TL;DR: It is shown that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites.
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