title: Immune and Stromal Classification of Colorectal Cancer Is Associated with Molecular Subtypes and Relevant for Precision Immunotherapy.
abstract: OBJECTIVE
  The tumor microenvironment is formed by many distinct and interacting cell populations, and its composition may predict patients' prognosis and response to therapies. Colorectal cancer is a heterogeneous disease in which immune classifications and four consensus molecular subgroups (CMS) have been described. Our aim was to integrate the composition of the tumor microenvironment with the consensus molecular classification of colorectal cancer.
  
  
  METHODS
  We retrospectively analyzed the composition and the functional orientation of the immune, fibroblastic, and angiogenic microenvironment of 1,388 colorectal cancer tumors from three independent cohorts using transcriptomics. We validated our findings using immunohistochemistry.
  
  
  RESULTS
  We report that colorectal cancer molecular subgroups and microenvironmental signatures are highly correlated. Out of the four molecular subgroups, two highly express immune-specific genes. The good-prognosis microsatellite instable-enriched subgroup (CMS1) is characterized by overexpression of genes specific to cytotoxic lymphocytes. In contrast, the poor-prognosis mesenchymal subgroup (CMS4) expresses markers of lymphocytes and of cells of monocytic origin. The mesenchymal subgroup also displays an angiogenic, inflammatory, and immunosuppressive signature, a coordinated pattern that we also found in breast (n = 254), ovarian (n = 97), lung (n = 80), and kidney (n = 143) cancers. Pathologic examination revealed that the mesenchymal subtype is characterized by a high density of fibroblasts that likely produce the chemokines and cytokines that favor tumor-associated inflammation and support angiogenesis, resulting in a poor prognosis. In contrast, the canonical (CMS2) and metabolic (CMS3) subtypes with intermediate prognosis exhibit low immune and inflammatory signatures.
  
  
  CONCLUSIONS
  The distinct immune orientations of the colorectal cancer molecular subtypes pave the way for tailored immunotherapies. Clin Cancer Res; 22(16); 4057-66. ©2016 AACR.
authors.affiliation: INSERM UMR_S 1138, Cancer, Immune Control and Escape, Cordeliers Research Centre, Paris, France. Université Paris Descartes, Paris, France. Université Pierre et Marie Curie, Paris, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Becht
authors.affiliation: Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: de Reyniès
authors.affiliation: INSERM UMR_S 1138, Cancer, Immune Control and Escape, Cordeliers Research Centre, Paris, France. Université Paris Descartes, Paris, France. Université Pierre et Marie Curie, Paris, France.
authors.forename: Nicolas A
authors.initials: NA
authors.lastname: Giraldo
authors.affiliation: Université Paris Descartes, Paris, France. INSERM, UMR_S1147, Paris, France.
authors.forename: Camilla
authors.initials: C
authors.lastname: Pilati
authors.affiliation: INSERM UMR_S 1138, Cancer, Immune Control and Escape, Cordeliers Research Centre, Paris, France. Université Paris Descartes, Paris, France. Université Pierre et Marie Curie, Paris, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Buttard
authors.affiliation: INSERM UMR_S 1138, Cancer, Immune Control and Escape, Cordeliers Research Centre, Paris, France. Université Paris Descartes, Paris, France. Université Pierre et Marie Curie, Paris, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Lacroix
authors.affiliation: Centre de Recherche en Cancérologie de Toulouse, Unité Mixte de Recherche, 1037 INSERM - Université Toulouse III, Toulouse, France. Department of Pathology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
authors.forename: Janick
authors.initials: J
authors.lastname: Selves
authors.affiliation: INSERM UMR_S 1138, Cancer, Immune Control and Escape, Cordeliers Research Centre, Paris, France. Université Paris Descartes, Paris, France. Université Pierre et Marie Curie, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Sautès-Fridman
authors.affiliation: Université Paris Descartes, Paris, France. INSERM, UMR_S1147, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.affiliation: INSERM UMR_S 1138, Cancer, Immune Control and Escape, Cordeliers Research Centre, Paris, France. Université Paris Descartes, Paris, France. Université Pierre et Marie Curie, Paris, France. herve.fridman@crc.jussieu.fr.
authors.forename: Wolf Herman
authors.initials: WH
authors.lastname: Fridman
mesh_terms: D014408:Biomarkers, Tumor; D000072645:Cancer-Associated Fibroblasts / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D020869:Gene Expression Profiling; D006801:Humans; D007167:Immunotherapy; D009389:Neovascularization, Pathologic; D057285:Precision Medicine; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology
chemical_list: D014408:Biomarkers, Tumor