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      Integrative Analyses of Colorectal Cancer Show Immunoscore Is a Stronger Predictor of Patient Survival Than Microsatellite Instability.

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          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.

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          Author and article information

          Journal
          Immunity
          Immunity
          1097-4180
          1074-7613
          Mar 15 2016
          : 44
          : 3
          Affiliations
          [1 ] 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.
          [2 ] 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.
          [3 ] 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.
          [4 ] 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.
          [5 ] 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.
          [6 ] Biocenter, Division of Bioinformatics, Innsbruck Medical University, 6020 Innsbruck, Austria.
          [7 ] Institute of Human Genetics, Medical University of Graz, 8010 Graz, Austria.
          [8 ] INSERM, U1079, Faculté de Médecine, Université de Rouen and the Institute for Research and Innovation in Biomedecine (IRIB), 76000 Rouen, France.
          [9 ] 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.
          [10 ] Department of Anatomopathology, Hôpital Européen Georges-Pompidou, Assistance Publique-Hopitaux de Paris, 75015 Paris, France.
          [11 ] Department of Digestive Surgery, Rouen University Hospital, 76000 Rouen, France.
          [12 ] Department of Anatomopathology, Rouen University Hospital, 76000 Rouen, France.
          [13 ] Department of Anatomopathology, Rouen University Hospital, 76000 Rouen, France; Department of Gastroenterology, Le Havre Hospital, 76600 Le Havre, France.
          [14 ] Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, 3263 Doha, Qatar.
          [15 ] UMRS1138, Université Paris Descartes - Sorbonne Paris Cité, 75006 Paris, France; INSERM, UMRS775, Bases Moléculaires de la Réponse aux Xénobiotiques, 75006 Paris, France.
          [16 ] Department of Gastroenterology, Rouen University Hospital, 76000 Rouen, France.
          [17 ] 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.
          [18 ] 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.
          [19 ] Innovative Medicines and Early Development, Oncology, AstraZeneca, CB4 OWG Cambridge, UK; MedImmune, CB21 GGH Cambridge, UK.
          [20 ] 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.
          [21 ] 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.
          Article
          S1074-7613(16)30064-4
          10.1016/j.immuni.2016.02.025
          26982367
          46588df1-bcea-4ad3-9b56-b6ad1a42dc67
          Copyright © 2016 Elsevier Inc. All rights reserved.
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