title: Integrative Analyses of Colorectal Cancer Show Immunoscore Is a Stronger Predictor of Patient Survival Than Microsatellite Instability.
abstract: 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. MSI tumors had increased frameshift mutations, showed genetic evidence of immunoediting, had higher densities of Th1, effector-memory T cells, in situ proliferating T cells, and inhibitory PD1-PDL1 cells, had high Immunoscores, and were infiltrated with mutation-specific cytotoxic T cells. Multivariate analysis revealed that Immunoscore was superior to microsatellite instability in predicting patients' disease-specific recurrence and survival. These findings indicate that assessment of the immune status via Immunoscore provides a potent indicator of tumor recurrence beyond microsatellite-instability staging that could be an important guide for immunotherapy strategies.
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, 75006 Paris, France; UMRS1138, Université Paris Descartes - Sorbonne Paris Cité, 75006 Paris, France; UMRS1138, Pierre and Marie Curie University (Paris 6) - Sorbonne Paris Cité, Centre de Recherche des Cordeliers, 75006 Paris, France.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Mlecnik
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, 75006 Paris, France; UMRS1138, Université Paris Descartes - Sorbonne Paris Cité, 75006 Paris, France; UMRS1138, Pierre and Marie Curie University (Paris 6) - Sorbonne Paris Cité, Centre de Recherche des Cordeliers, 75006 Paris, France.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Bindea
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, 75006 Paris, France; UMRS1138, Université Paris Descartes - Sorbonne Paris Cité, 75006 Paris, France; UMRS1138, Pierre and Marie Curie University (Paris 6) - Sorbonne Paris Cité, Centre de Recherche des Cordeliers, 75006 Paris, France; Innovative Medicines and Early Development, Oncology, AstraZeneca, CB4 OWG Cambridge, UK.
authors.forename: Helen K
authors.initials: HK
authors.lastname: Angell
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, 75006 Paris, France; UMRS1138, Université Paris Descartes - Sorbonne Paris Cité, 75006 Paris, France; UMRS1138, Pierre and Marie Curie University (Paris 6) - Sorbonne Paris Cité, Centre de Recherche des Cordeliers, 75006 Paris, France; INSERM, U1079, Faculté de Médecine, Université de Rouen and the Institute for Research and Innovation in Biomedecine (IRIB), 76000 Rouen, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Maby
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, 75006 Paris, France; UMRS1138, Université Paris Descartes - Sorbonne Paris Cité, 75006 Paris, France; UMRS1138, Pierre and Marie Curie University (Paris 6) - Sorbonne Paris Cité, Centre de Recherche des Cordeliers, 75006 Paris, France; Biocenter, Division of Bioinformatics, Innsbruck Medical University, 6020 Innsbruck, Austria.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Angelova
authors.affiliation: INSERM, U1079, Faculté de Médecine, Université de Rouen and the Institute for Research and Innovation in Biomedecine (IRIB), 76000 Rouen, France; Department of Gastroenterology, Rouen University Hospital, 76000 Rouen, France; Department of Genetics, Rouen University Hospital, 76000 Rouen, France.
authors.forename: David
authors.initials: D
authors.lastname: Tougeron
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, 75006 Paris, France; UMRS1138, Université Paris Descartes - Sorbonne Paris Cité, 75006 Paris, France; UMRS1138, Pierre and Marie Curie University (Paris 6) - Sorbonne Paris Cité, Centre de Recherche des Cordeliers, 75006 Paris, France.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Church
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, 75006 Paris, France; UMRS1138, Université Paris Descartes - Sorbonne Paris Cité, 75006 Paris, France; UMRS1138, Pierre and Marie Curie University (Paris 6) - Sorbonne Paris Cité, Centre de Recherche des Cordeliers, 75006 Paris, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Lafontaine
authors.affiliation: Biocenter, Division of Bioinformatics, Innsbruck Medical University, 6020 Innsbruck, Austria.
authors.forename: Maria
authors.initials: M
authors.lastname: Fischer
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, 75006 Paris, France; UMRS1138, Université Paris Descartes - Sorbonne Paris Cité, 75006 Paris, France; UMRS1138, Pierre and Marie Curie University (Paris 6) - Sorbonne Paris Cité, Centre de Recherche des Cordeliers, 75006 Paris, France.
authors.forename: Tessa
authors.initials: T
authors.lastname: Fredriksen
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, 75006 Paris, France; UMRS1138, Université Paris Descartes - Sorbonne Paris Cité, 75006 Paris, France; UMRS1138, Pierre and Marie Curie University (Paris 6) - Sorbonne Paris Cité, Centre de Recherche des Cordeliers, 75006 Paris, France.
authors.forename: Maristella
authors.initials: M
authors.lastname: Sasso
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, 75006 Paris, France; UMRS1138, Université Paris Descartes - Sorbonne Paris Cité, 75006 Paris, France; UMRS1138, Pierre and Marie Curie University (Paris 6) - Sorbonne Paris Cité, Centre de Recherche des Cordeliers, 75006 Paris, France.
authors.forename: Amélie M
authors.initials: AM
authors.lastname: Bilocq
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, 75006 Paris, France; UMRS1138, Université Paris Descartes - Sorbonne Paris Cité, 75006 Paris, France; UMRS1138, Pierre and Marie Curie University (Paris 6) - Sorbonne Paris Cité, Centre de Recherche des Cordeliers, 75006 Paris, France.
authors.forename: Amos
authors.initials: A
authors.lastname: Kirilovsky
authors.affiliation: Institute of Human Genetics, Medical University of Graz, 8010 Graz, Austria.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Obenauf
authors.affiliation: INSERM, U1079, Faculté de Médecine, Université de Rouen and the Institute for Research and Innovation in Biomedecine (IRIB), 76000 Rouen, France.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Hamieh
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, 75006 Paris, France; Department of General and Digestive Surgery, Hôpital Européen Georges-Pompidou, Assistance Publique-Hopitaux de Paris, 75015 Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Berger
authors.affiliation: Department of Anatomopathology, Hôpital Européen Georges-Pompidou, Assistance Publique-Hopitaux de Paris, 75015 Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.affiliation: Department of Digestive Surgery, Rouen University Hospital, 76000 Rouen, France.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Tuech
authors.affiliation: Department of Anatomopathology, Rouen University Hospital, 76000 Rouen, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Sabourin
authors.affiliation: Department of Anatomopathology, Rouen University Hospital, 76000 Rouen, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Le Pessot
authors.affiliation: Department of Anatomopathology, Rouen University Hospital, 76000 Rouen, France; Department of Gastroenterology, Le Havre Hospital, 76600 Le Havre, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Mauillon
authors.affiliation: Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, 3263 Doha, Qatar.
authors.forename: Arash
authors.initials: A
authors.lastname: Rafii
authors.affiliation: UMRS1138, Université Paris Descartes - Sorbonne Paris Cité, 75006 Paris, France; INSERM, UMRS775, Bases Moléculaires de la Réponse aux Xénobiotiques, 75006 Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.affiliation: Institute of Human Genetics, Medical University of Graz, 8010 Graz, Austria.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Speicher
authors.affiliation: Biocenter, Division of Bioinformatics, Innsbruck Medical University, 6020 Innsbruck, Austria.
authors.forename: Zlatko
authors.initials: Z
authors.lastname: Trajanoski
authors.affiliation: Department of Gastroenterology, Rouen University Hospital, 76000 Rouen, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Michel
authors.affiliation: INSERM, U1079, Faculté de Médecine, Université de Rouen and the Institute for Research and Innovation in Biomedecine (IRIB), 76000 Rouen, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Sesboüe
authors.affiliation: INSERM, U1079, Faculté de Médecine, Université de Rouen and the Institute for Research and Innovation in Biomedecine (IRIB), 76000 Rouen, France; INSERM, UMRS775, Bases Moléculaires de la Réponse aux Xénobiotiques, 75006 Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Frebourg
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, 75006 Paris, France; UMRS1138, Université Paris Descartes - Sorbonne Paris Cité, 75006 Paris, France; UMRS1138, Pierre and Marie Curie University (Paris 6) - Sorbonne Paris Cité, Centre de Recherche des Cordeliers, 75006 Paris, France; Department of Immunology, Hôpital Européen Georges-Pompidou, Assistance Publique-Hopitaux de Paris, 75015 Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Pagès
authors.affiliation: Innovative Medicines and Early Development, Oncology, AstraZeneca, CB4 OWG Cambridge, UK; MedImmune, CB21 GGH Cambridge, UK.
authors.forename: Viia
authors.initials: V
authors.lastname: Valge-Archer
authors.affiliation: INSERM, U1079, Faculté de Médecine, Université de Rouen and the Institute for Research and Innovation in Biomedecine (IRIB), 76000 Rouen, France; Department of Genetics, Rouen University Hospital, 76000 Rouen, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Latouche
authors.affiliation: INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, 75006 Paris, France; UMRS1138, Université Paris Descartes - Sorbonne Paris Cité, 75006 Paris, France; UMRS1138, Pierre and Marie Curie University (Paris 6) - Sorbonne Paris Cité, Centre de Recherche des Cordeliers, 75006 Paris, France. Electronic address: jerome.galon@crc.jussieu.fr.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Galon
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000401:mortality; D003601:Cytotoxicity Tests, Immunologic; D004252:DNA Mutational Analysis; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D006801:Humans; D007118:Immunoassay / Q000379:methods*; D007156:Immunologic Memory; D008297:Male; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D057089:Pathology, Molecular / Q000379:methods*; D011237:Predictive Value of Tests; D011379:Prognosis; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D059467:Transcriptome