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JOURNAL ARTICLE
Mihaela Angelova, Bernhard Mlecnik, Angela Vasaturo, Gabriela Bindea, Tessa Fredriksen, Lucie Lafontaine, Bénédicte Buttard, Erwan Morgand, Daniela Bruni, Anne Jouret-Mourin, Catherine Hubert, Alex Kartheuser, Yves Humblet, Michele Ceccarelli, Najeeb Syed, Francesco M Marincola, Davide Bedognetti, Marc Van den Eynde, Jérôme Galon
We examined how the immune microenvironment molds tumor evolution at different metastatic organs in a longitudinal dataset of colorectal cancer. Through multiplexed analyses, we showed that clonal evolution patterns during metastatic progression depend on the immune contexture at the metastatic site. Genetic evidence of neoantigen depletion was observed in the sites with high Immunoscore and spatial proximity between Ki67+ tumor cells and CD3+ cells. The immunoedited tumor clones were eliminated and did not recur, while progressing clones were immune privileged, despite the presence of tumor-infiltrating lymphocytes...
October 18, 2018: Cell
#22
JOURNAL ARTICLE
Franck Pagès, Bernhard Mlecnik, Florence Marliot, Gabriela Bindea, Fang-Shu Ou, Carlo Bifulco, Alessandro Lugli, Inti Zlobec, Tilman T Rau, Martin D Berger, Iris D Nagtegaal, Elisa Vink-Börger, Arndt Hartmann, Carol Geppert, Julie Kolwelter, Susanne Merkel, Robert Grützmann, Marc Van den Eynde, Anne Jouret-Mourin, Alex Kartheuser, Daniel Léonard, Christophe Remue, Julia Y Wang, Prashant Bavi, Michael H A Roehrl, Pamela S Ohashi, Linh T Nguyen, SeongJun Han, Heather L MacGregor, Sara Hafezi-Bakhtiari, Bradly G Wouters, Giuseppe V Masucci, Emilia K Andersson, Eva Zavadova, Michal Vocka, Jan Spacek, Lubos Petruzelka, Bohuslav Konopasek, Pavel Dundr, Helena Skalova, Kristyna Nemejcova, Gerardo Botti, Fabiana Tatangelo, Paolo Delrio, Gennaro Ciliberto, Michele Maio, Luigi Laghi, Fabio Grizzi, Tessa Fredriksen, Bénédicte Buttard, Mihaela Angelova, Angela Vasaturo, Pauline Maby, Sarah E Church, Helen K Angell, Lucie Lafontaine, Daniela Bruni, Carine El Sissy, Nacilla Haicheur, Amos Kirilovsky, Anne Berger, Christine Lagorce, Jeffrey P Meyers, Christopher Paustian, Zipei Feng, Carmen Ballesteros-Merino, Jeroen Dijkstra, Carlijn van de Water, Shannon van Lent-van Vliet, Nikki Knijn, Ana-Maria Mușină, Dragos-Viorel Scripcariu, Boryana Popivanova, Mingli Xu, Tomonobu Fujita, Shoichi Hazama, Nobuaki Suzuki, Hiroaki Nagano, Kiyotaka Okuno, Toshihiko Torigoe, Noriyuki Sato, Tomohisa Furuhata, Ichiro Takemasa, Kyogo Itoh, Prabhu S Patel, Hemangini H Vora, Birva Shah, Jayendrakumar B Patel, Kruti N Rajvik, Shashank J Pandya, Shilin N Shukla, Yili Wang, Guanjun Zhang, Yutaka Kawakami, Francesco M Marincola, Paolo A Ascierto, Daniel J Sargent, Bernard A Fox, Jérôme Galon
BACKGROUND: The estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I-III colon cancer. METHODS: An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I-III colon cancer...
May 26, 2018: Lancet
#23
JOURNAL ARTICLE
Bernhard Mlecnik, Marc Van den Eynde, Gabriela Bindea, Sarah E Church, Angela Vasaturo, Tessa Fredriksen, Lucie Lafontaine, Nacilla Haicheur, Florence Marliot, Daphné Debetancourt, Géraldine Pairet, Anne Jouret-Mourin, Jean-Francois Gigot, Catherine Hubert, Etienne Danse, Cristina Dragean, Javier Carrasco, Yves Humblet, Viia Valge-Archer, Anne Berger, Franck Pagès, Jean-Pascal Machiels, Jérôme Galon
Background: This study assesses how the metastatic immune landscape is impacting the response to treatment and the outcome of colorectal cancer (CRC) patients. Methods: Complete curative resection of metastases (n = 441) was performed for two patient cohorts (n = 153). Immune densities were quantified in the center and invasive margin of all metastases. Immunoscore and T and B cell (TB) score were analyzed in relation to radiological and pathological responses and patient's disease-free (DFS) and overall survival (OS) using multivariable Cox proportional hazards models...
January 1, 2018: Journal of the National Cancer Institute
#24
JOURNAL ARTICLE
Bernhard Mlecnik, Jérôme Galon, Gabriela Bindea
The interpretation of high dimensional datasets resulting from genomic and proteomic experiments in a timely and efficient manner is challenging. ClueGO software is a Cytoscape App that extracts representative functional biological information for large lists of genes or proteins. The functional enrichment analysis is based on the latest publicly available data from multiple annotation and ontology resources that can be automatically accessed through ClueGO. Predefined settings for the selection of the terms are provided to facilitate the analysis...
January 16, 2018: Journal of Proteomics
#25
JOURNAL ARTICLE
Ilaria Marigo, Serena Zilio, Giacomo Desantis, Bernhard Mlecnik, Andrielly H R Agnellini, Stefano Ugel, Maria Stella Sasso, Joseph E Qualls, Franz Kratochvill, Paola Zanovello, Barbara Molon, Carola H Ries, Valeria Runza, Sabine Hoves, Amélie M Bilocq, Gabriela Bindea, Emilia M C Mazza, Silvio Bicciato, Jérôme Galon, Peter J Murray, Vincenzo Bronte
No abstract text is available yet for this article.
October 10, 2016: Cancer Cell
#26
JOURNAL ARTICLE
Ilaria Marigo, Serena Zilio, Giacomo Desantis, Bernhard Mlecnik, Andrielly H R Agnellini, Stefano Ugel, Maria Stella Sasso, Joseph E Qualls, Franz Kratochvill, Paola Zanovello, Barbara Molon, Carola H Ries, Valeria Runza, Sabine Hoves, Amélie M Bilocq, Gabriela Bindea, Emilia M C Mazza, Silvio Bicciato, Jérôme Galon, Peter J Murray, Vincenzo Bronte
Effective cancer immunotherapy requires overcoming immunosuppressive tumor microenvironments. We found that local nitric oxide (NO) production by tumor-infiltrating myeloid cells is important for adoptively transferred CD8(+) cytotoxic T cells to destroy tumors. These myeloid cells are phenotypically similar to inducible nitric oxide synthase (NOS2)- and tumor necrosis factor (TNF)-producing dendritic cells (DC), or Tip-DCs. Depletion of immunosuppressive, colony stimulating factor 1 receptor (CSF-1R)-dependent arginase 1(+) myeloid cells enhanced NO-dependent tumor killing...
September 12, 2016: Cancer Cell
#27
COMPARATIVE STUDY
Bernhard Mlecnik, Gabriela Bindea, Helen K Angell, Pauline Maby, Mihaela Angelova, David Tougeron, Sarah E Church, Lucie Lafontaine, Maria Fischer, Tessa Fredriksen, Maristella Sasso, Amélie M Bilocq, Amos Kirilovsky, Anna C Obenauf, Mohamad Hamieh, Anne Berger, Patrick Bruneval, Jean-Jacques Tuech, Jean-Christophe Sabourin, Florence Le Pessot, Jacques Mauillon, Arash Rafii, Pierre Laurent-Puig, Michael R Speicher, Zlatko Trajanoski, Pierre Michel, Richard Sesboüe, Thierry Frebourg, Franck Pagès, Viia Valge-Archer, Jean-Baptiste Latouche, Jérôme Galon
Microsatellite instability in colorectal cancer predicts favorable outcomes. However, the mechanistic relationship between microsatellite instability, tumor-infiltrating immune cells, Immunoscore, and their impact on patient survival remains to be elucidated. We found significant differences in mutational patterns, chromosomal instability, and gene expression that correlated with patient microsatellite instability status. A prominent immune gene expression was observed in microsatellite-instable (MSI) tumors, as well as in a subgroup of microsatellite-stable (MSS) tumors...
March 15, 2016: Immunity
#28
Anna S Berghoff, Elisabeth Fuchs, Gerda Ricken, Bernhard Mlecnik, Gabriela Bindea, Thomas Spanberger, Monika Hackl, Georg Widhalm, Karin Dieckmann, Daniela Prayer, Amelie Bilocq, Harald Heinzl, Christoph Zielinski, Rupert Bartsch, Peter Birner, Jerome Galon, Matthias Preusser
The immune microenvironment of the brain differs from that of other organs and the role of tumor-infiltrating lymphocytes (TILs) in brain metastases (BM), one of the most common and devastating complication of cancer, is unclear. We investigated TIL subsets and their prognostic impact in 116 BM specimens using immunohistochemistry for CD3, CD8, CD45RO, FOXP3, PD1 and PD-L1. The Immunoscore was calculated as published previously. Overall, we found TIL infiltration in 115/116 (99.1%) BM specimens. PD-L1 expression was evident in 19/67 (28...
2016: Oncoimmunology
#29
JOURNAL ARTICLE
Bernhard Mlecnik, Gabriela Bindea, Amos Kirilovsky, Helen K Angell, Anna C Obenauf, Marie Tosolini, Sarah E Church, Pauline Maby, Angela Vasaturo, Mihaela Angelova, Tessa Fredriksen, Stéphanie Mauger, Maximilian Waldner, Anne Berger, Michael R Speicher, Franck Pagès, Viia Valge-Archer, Jérôme Galon
Although distant metastases account for most of the deaths in cancer patients, fundamental questions regarding mechanisms that promote or inhibit metastasis remain unanswered. We show the impact of mutations, genomic instability, lymphatic and blood vascularization, and the immune contexture of the tumor microenvironment on synchronous metastases in large cohorts of colorectal cancer patients. We observed large genetic heterogeneity among primary tumors, but no major differences in chromosomal instability or key cancer-associated mutations...
February 24, 2016: Science Translational Medicine
#30
JOURNAL ARTICLE
Pauline Maby, David Tougeron, Mohamad Hamieh, Bernhard Mlecnik, Hafid Kora, Gabriela Bindea, Helen K Angell, Tessa Fredriksen, Nicolas Elie, Emilie Fauquembergue, Aurélie Drouet, Jérôme Leprince, Jacques Benichou, Jacques Mauillon, Florence Le Pessot, Richard Sesboüé, Jean-Jacques Tuech, Jean-Christophe Sabourin, Pierre Michel, Thierry Frébourg, Jérôme Galon, Jean-Baptiste Latouche
Colorectal cancers with microsatellite instability (MSI) represent 15% of all colorectal cancers, including Lynch syndrome as the most frequent hereditary form of this disease. Notably, MSI colorectal cancers have a higher density of tumor-infiltrating lymphocytes (TIL) than other colorectal cancers. This feature is thought to reflect the accumulation of frameshift mutations in sequences that are repeated within gene coding regions, thereby leading to the synthesis of neoantigens recognized by CD8(+) T cells...
September 1, 2015: Cancer Research
#31
JOURNAL ARTICLE
Gautier Stoll, Gabriela Bindea, Bernhard Mlecnik, Jérôme Galon, Laurence Zitvogel, Guido Kroemer
Anticancer immunosurveillance is one of the major endogenous breaks of tumor progression. Here, we analyzed gene expression pattern indicative of the presence of distinct leukocyte subtypes within four cancer types (breast cancer, colorectal carcinoma, melanoma, and non-small cell lung cancer) and 20 different microarray datasets corresponding to a total of 3471 patients. Multiple metagenes reflecting the presence of such immune cell subtypes were highly reproducible across distinct cohorts. Nonetheless, there were sizable differences in the correlation patterns among such immune-relevant metagenes across distinct malignancies...
May 20, 2015: Oncotarget
#32
JOURNAL ARTICLE
Mihaela Angelova, Pornpimol Charoentong, Hubert Hackl, Maria L Fischer, Rene Snajder, Anne M Krogsdam, Maximilian J Waldner, Gabriela Bindea, Bernhard Mlecnik, Jerome Galon, Zlatko Trajanoski
BACKGROUND: While large-scale cancer genomic projects are comprehensively characterizing the mutational spectrum of various cancers, so far little attention has been devoted to either define the antigenicity of these mutations or to characterize the immune responses they elicit. Here we present a strategy to characterize the immunophenotypes and the antigen-ome of human colorectal cancer. RESULTS: We apply our strategy to a large colorectal cancer cohort (n = 598) and show that subpopulations of tumor-infiltrating lymphocytes are associated with distinct molecular phenotypes...
March 31, 2015: Genome Biology
#33
REVIEW
Jérôme Galon, Gabriela Bindea, Bernhard Mlecnik, Helen Angell, Christine Lagorce, Ana Maria Todosi, Anne Berger, Franck Pagès
The natural history of cancer involves interactions between the tumor and the host immune system. In humans, clinical and experimental data support the existence of a natural immune response against cancer. We provided evidence that the type, the density and the location of immune cells within the tumor strongly influence the prognosis, independently of the TNM classification. We established a methodology named "immunoscore" to assess in clinical practice the immune infiltrate. An international consortium of expert laboratories is currently testing the immunoscore in routine clinical settings for cancer classification...
April 2014: Médecine Sciences: M/S
#34
Gabriela Bindea, Bernhard Mlecnik, Helen K Angell, Jérôme Galon
Understanding the spontaneous immune response of cancer patients is critical for the design of efficient anticancer immunotherapies. The power of integrative tumor immunology approaches allowed for a comprehensive view of the immune system evolution in the course of tumor progression and recurrence. We have demonstrated that tumor-infiltrating immune cells are spatiotemporally regulated, a finding that has profound implications for the development of efficient anticancer immunotherapies.
January 1, 2014: Oncoimmunology
#35
Gautier Stoll, David Enot, Bernhard Mlecnik, Jérôme Galon, Laurence Zitvogel, Guido Kroemer
There is ample evidence that neoadjuvant chemotherapy of breast carcinoma is particularly efficient if the tumor presents signs of either a pre-existent or therapy-induced anticancer immune response. Antineoplastic chemotherapies are particularly beneficial if they succeed in inducing immunogenic cell death, hence converting the tumor into its own therapeutic vaccine. Immunogenic cell death is characterized by a pre-mortem stress response including endoplasmic reticulum stress and autophagy. Based on these premises, we attempted to identify metagenes that reflect an intratumoral immune response or local stress responses in the transcriptomes of breast cancer patients...
January 1, 2014: Oncoimmunology
#36
JOURNAL ARTICLE
Maria-Gabriela Anitei, Guy Zeitoun, Bernhard Mlecnik, Florence Marliot, Nacilla Haicheur, Ana-Maria Todosi, Amos Kirilovsky, Christine Lagorce, Gabriela Bindea, Dan Ferariu, Mihai Danciu, Patrick Bruneval, Viorel Scripcariu, Jean-Marc Chevallier, Franck Zinzindohoué, Anne Berger, Jérôme Galon, Franck Pagès
PURPOSE: To determine whether the tumor immune infiltrate, as recently evaluated with the Immunoscore methodology, could be a useful prognostic marker in patients with rectal cancers. EXPERIMENTAL DESIGN: The influence of the immune infiltrate on patient's outcome was investigated in patients with or without preoperative chemoradiation therapy (pCRT). The density of total (CD3(+)) and cytotoxic (CD8(+)) T lymphocytes was evaluated by immunohistochemistry and quantified by a dedicated image analysis software in surgical specimens of patients with rectal cancer (n = 111) who did not receive pCRT and in tumor biopsies performed before pCRT from additional 55 patients...
April 1, 2014: Clinical Cancer Research
#37
JOURNAL ARTICLE
Bernhard Mlecnik, Gabriela Bindea, Helen K Angell, Maria Stella Sasso, Anna C Obenauf, Tessa Fredriksen, Lucie Lafontaine, Amelie M Bilocq, Amos Kirilovsky, Marie Tosolini, Maximilian Waldner, Anne Berger, Wolf Herman Fridman, Arash Rafii, Viia Valge-Archer, Franck Pagès, Michael R Speicher, Jérôme Galon
The tumor microenvironment is host to a complex network of cytokines that contribute to shaping the intratumoral immune reaction. Chromosomal gains and losses, coupled with expression analysis, of 59 cytokines and receptors and their functional networks were investigated in colorectal cancers. Changes in local expression for 13 cytokines were shown. Metastatic patients exhibited an increased frequency of deletions of cytokines from chromosome 4. Interleukin 15 (IL15) deletion corresponded with decreased IL15 expression, a higher risk of tumor recurrence, and reduced patient survival...
March 19, 2014: Science Translational Medicine
#38
JOURNAL ARTICLE
Gabriela Bindea, Bernhard Mlecnik, Marie Tosolini, Amos Kirilovsky, Maximilian Waldner, Anna C Obenauf, Helen Angell, Tessa Fredriksen, Lucie Lafontaine, Anne Berger, Patrick Bruneval, Wolf Herman Fridman, Christoph Becker, Franck Pagès, Michael R Speicher, Zlatko Trajanoski, Jérôme Galon
The complex interactions between tumors and their microenvironment remain to be elucidated. Combining large-scale approaches, we examined the spatio-temporal dynamics of 28 different immune cell types (immunome) infiltrating tumors. We found that the immune infiltrate composition changed at each tumor stage and that particular cells had a major impact on survival. Densities of T follicular helper (Tfh) cells and innate cells increased, whereas most T cell densities decreased along with tumor progression. The number of B cells, which are key players in the core immune network and are associated with prolonged survival, increased at a late stage and showed a dual effect on recurrence and tumor progression...
October 17, 2013: Immunity
#39
REVIEW
Jérôme Galon, Bernhard Mlecnik, Gabriela Bindea, Helen K Angell, Anne Berger, Christine Lagorce, Alessandro Lugli, Inti Zlobec, Arndt Hartmann, Carlo Bifulco, Iris D Nagtegaal, Richard Palmqvist, Giuseppe V Masucci, Gerardo Botti, Fabiana Tatangelo, Paolo Delrio, Michele Maio, Luigi Laghi, Fabio Grizzi, Martin Asslaber, Corrado D'Arrigo, Fernando Vidal-Vanaclocha, Eva Zavadova, Lotfi Chouchane, Pamela S Ohashi, Sara Hafezi-Bakhtiari, Bradly G Wouters, Michael Roehrl, Linh Nguyen, Yutaka Kawakami, Shoichi Hazama, Kiyotaka Okuno, Shuji Ogino, Peter Gibbs, Paul Waring, Noriyuki Sato, Toshihiko Torigoe, Kyogo Itoh, Prabhu S Patel, Shilin N Shukla, Yili Wang, Scott Kopetz, Frank A Sinicrope, Viorel Scripcariu, Paolo A Ascierto, Francesco M Marincola, Bernard A Fox, Franck Pagès
The American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) TNM staging system provides the most reliable guidelines for the routine prognostication and treatment of colorectal carcinoma. This traditional tumour staging summarizes data on tumour burden (T), the presence of cancer cells in draining and regional lymph nodes (N) and evidence for distant metastases (M). However, it is now recognized that the clinical outcome can vary significantly among patients within the same stage...
January 2014: Journal of Pathology
#40
JOURNAL ARTICLE
Gabriela Bindea, Jérôme Galon, Bernhard Mlecnik
SUMMARY: The CluePedia Cytoscape plugin is a search tool for new markers potentially associated to pathways. CluePedia calculates linear and non-linear statistical dependencies from experimental data. Genes, proteins and miRNAs can be connected based on in silico and/or experimental information and integrated into a ClueGO network of terms/pathways. Interrelations within each pathway can be investigated, and new potential associations may be revealed through gene/protein/miRNA enrichments...
March 1, 2013: Bioinformatics
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