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      Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours

      research-article
      1 , 2 , 3 , 1 , 2 , 3 , 1 , 2 , 3 , 1 , 2 , 3 , 4 , 5 , 6 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 12 , 13 , 14 , 15 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 31 , 32 , 33 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 1 , 2 , 3 , 42
      The Journal of Pathology
      John Wiley & Sons, Ltd
      Immunoscore, colorectal cancer, colon carcinoma, tumour microenvironment, immune response, classification, prognostic markers, predictive markers, T cells

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          Abstract

          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. The current classification provides limited prognostic information and does not predict response to therapy. Multiple ways to classify cancer and to distinguish different subtypes of colorectal cancer have been proposed, including morphology, cell origin, molecular pathways, mutation status and gene expression-based stratification. These parameters rely on tumour-cell characteristics. Extensive literature has investigated the host immune response against cancer and demonstrated the prognostic impact of the in situ immune cell infiltrate in tumours. A methodology named ‘Immunoscore’ has been defined to quantify the in situ immune infiltrate. In colorectal cancer, the Immunoscore may add to the significance of the current AJCC/UICC TNM classification, since it has been demonstrated to be a prognostic factor superior to the AJCC/UICC TNM classification. An international consortium has been initiated to validate and promote the Immunoscore in routine clinical settings. The results of this international consortium may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune). © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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          Most cited references47

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          Effector memory T cells, early metastasis, and survival in colorectal cancer.

          The role of tumor-infiltrating immune cells in the early metastatic invasion of colorectal cancer is unknown. We studied pathological signs of early metastatic invasion (venous emboli and lymphatic and perineural invasion) in 959 specimens of resected colorectal cancer. The local immune response within the tumor was studied by flow cytometry (39 tumors), low-density-array real-time polymerase-chain-reaction assay (75 tumors), and tissue microarrays (415 tumors). Univariate analysis showed significant differences in disease-free and overall survival according to the presence or absence of histologic signs of early metastatic invasion (P<0.001). Multivariate Cox analysis showed that an early conventional pathological tumor-node-metastasis stage (P<0.001) and the absence of early metastatic invasion (P=0.04) were independently associated with increased survival. As compared with tumors with signs of early metastatic invasion, tumors without such signs had increased infiltrates of immune cells and increased levels of messenger RNA (mRNA) for products of type 1 helper effector T cells (CD8, T-BET [T-box transcription factor 21], interferon regulatory factor 1, interferon-gamma, granulysin, and granzyme B) but not increased levels of inflammatory mediators or immunosuppressive molecules. The two types of tumors had significant differences in the levels of expression of 65 combinations of T-cell markers, and hierarchical clustering showed that markers of T-cell migration, activation, and differentiation were increased in tumors without signs of early metastatic invasion. The latter type of tumors also had increased numbers of CD8+ T cells, ranging from early memory (CD45RO+CCR7-CD28+CD27+) to effector memory (CD45RO+CCR7-CD28-CD27-) T cells. The presence of high levels of infiltrating memory CD45RO+ cells, evaluated immunohistochemically, correlated with the absence of signs of early metastatic invasion, a less advanced pathological stage, and increased survival. Signs of an immune response within colorectal cancers are associated with the absence of pathological evidence of early metastatic invasion and with prolonged survival. Copyright 2005 Massachusetts Medical Society.
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            Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer.

            The tumor microenvironment includes a complex network of immune T-cell subpopulations. In this study, we systematically analyzed the balance between cytotoxic T cells and different subsets of helper T cells in human colorectal cancers and we correlated their impact on disease-free survival. A panel of immune related genes were analyzed in 125 frozen colorectal tumor specimens. Infiltrating cytotoxic T cells, Treg, Th1, and Th17 cells were also quantified in the center and the invasive margin of the tumors. By hierarchical clustering of a correlation matrix we identified functional clusters of genes associated with Th17 (RORC, IL17A), Th2 (IL4, IL5, IL13), Th1 (Tbet, IRF1, IL12Rb2, STAT4), and cytotoxicity (GNLY, GZMB, PRF1). Patients with high expression of the Th17 cluster had a poor prognosis, whereas patients with high expression of the Th1 cluster had prolonged disease-free survival. In contrast, none of the Th2 clusters were predictive of prognosis. Combined analysis of cytotoxic/Th1 and Th17 clusters improved the ability to discriminate relapse. In situ analysis of the density of IL17+ cells and CD8+ cells in tumor tissues confirmed the results. Our findings argue that functional Th1 and Th17 clusters yield opposite effects on patient survival in colorectal cancer, and they provide complementary information that may improve prognosis. ©2011 AACR.
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              Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer.

              To determine the prognostic significance of FOXP3(+) lymphocyte (Treg) density in colorectal cancer compared with conventional histopathologic features and with CD8(+) and CD45RO(+) lymphocyte densities. Tissue microarrays and immunohistochemistry were used to assess the densities of CD8(+), CD45RO(+), and FOXP3(+) lymphocytes in tumor tissue and normal colonic mucosa from 967 stage II and stage III colorectal cancers. These were evaluated for associations with histopathologic features and patient survival. FOXP3(+) Treg density was higher in tumor tissue compared with normal colonic mucosa, whereas CD8(+) and CD45RO(+) cell densities were lower. FOXP3(+) Tregs were not associated with any histopathologic features, with the exception of tumor stage. Multivariate analysis showed that stage, vascular invasion, and FOXP3(+) Treg density in normal and tumor tissue were independent prognostic indicators, but not CD8(+) and CD45RO(+). High FOXP3(+) Treg density in normal mucosa was associated with worse prognosis (hazard ratio [HR] = 1.51; 95% CI, 1.07 to 2.13; P = .019). In contrast, a high density of FOXP3(+) Tregs in tumor tissue was associated with improved survival (HR = 0.54; 95% CI, 0.38 to 0.77; P = .001). FOXP3(+) Treg density in normal and tumor tissue had stronger prognostic significance in colorectal cancer compared with CD8(+) and CD45RO(+) lymphocytes. The finding of improved survival associated with a high density of tumor-infiltrating FOXP3(+) Tregs in colorectal cancer contrasts with several other solid cancer types. The inclusion of FOXP3(+) Treg density may help to improve the prognostication of early-stage colorectal cancer.
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                Author and article information

                Journal
                J Pathol
                J. Pathol
                path
                The Journal of Pathology
                John Wiley & Sons, Ltd (Chichester, UK )
                0022-3417
                1096-9896
                January 2014
                10 December 2013
                : 232
                : 2
                : 199-209
                Affiliations
                [1 ]INSERM, U872, Laboratory of Integrative Cancer Immunology Paris, France
                [2 ]Université Paris Descartes Paris, France
                [3 ]Centre de Recherche des Cordeliers Université Pierre et Marie Curie Paris 6, France
                [4 ]Digestive Surgery Department, Georges Pompidou European Hospital Paris, France
                [5 ]Department of Pathology, Avicenne Hospital Bobigny, France
                [6 ]Institute of Pathology, University of Bern Switzerland
                [7 ]Department of Pathology, University of Erlangen Germany
                [8 ]Department of Pathology, Providence Portland Medical Center Portland, OR, USA
                [9 ]Pathology Department, Radboud University Nijmegen Medical Centre The Netherlands
                [10 ]Department of Medical Biosciences, Pathology, Umea University Sweden
                [11 ]Department of Oncology–Pathology, Karolinska Institute Stockholm, Sweden
                [12 ]Department of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumouri, ‘Fondazione G Pascale’ Naples, Italy
                [13 ]Colorectal Surgery Department, Istituto Nazionale per lo Studio e la Cura dei Tumouri, ‘Fondazione G Pascale’ Naples, Italy
                [14 ]Division of Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumouri Siena, Italy
                [15 ]Molecular Gastroenterology and Department of Gastroenterology, Humanitas Clinical and Research Centre Rozzano, Milan, Italy
                [16 ]Institute of Pathology, Medical University of Graz Austria
                [17 ]Department of Histopathology, Dorset County Hospital Dorchester, UK
                [18 ]CEU-San Pablo University School of Medicine and HM Hospital of Madrid Scientific Foundation, Institute of Applied Molecular Medicine (IMMA) Madrid, Spain
                [19 ]Department of Oncology, Charles University in Prague, First Faculty of Medicine, Department of Oncology of the First Faculty of Medicine and General Hospital Prague, Czech Republic
                [20 ]Weill Cornell Medical College Doha, Qatar
                [21 ]Ontario Cancer Institute and Campbell Family Institute for Cancer Research, Princess Margaret Hospital, University Health Network Toronto, ON, Canada
                [22 ]Department of Pathology and Laboratory Medicine, University Health Network Toronto, ON, Canada
                [23 ]UHN Program in BioSpecimen Sciences, University Health Network Toronto, ON, Canada
                [24 ]Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network Toronto, ON, Canada
                [25 ]Division of Cellular Signalling, Institute for Advanced Medical Research, Keio University School of Medicine Tokyo, Japan
                [26 ]Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine Japan
                [27 ]Department of Surgery, Kinki University School of Medicine Osaka-sayama, Japan
                [28 ]Department of Pathology, Brigham and Women's Hospital, Harvard Medical School and Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA
                [29 ]Department of Medical Oncology, Royal Melbourne Hospital Australia
                [30 ]Department of Pathology, University of Melbourne Australia
                [31 ]Department of Pathology, Sapporo Medical University School of Medicine Japan
                [32 ]Department of Immunology and Immunotherapy, Kurume University School of Medicine Japan
                [33 ]The Gujarat Cancer and Research Institute Asarwa, Ahmedabad, India
                [34 ]Institute for Cancer Research, Centre of Translational Medicine, Xi'an Jiaotong University Xian, People's Republic of China
                [35 ]MD Anderson Cancer Center Houston, TX, USA
                [36 ]Mayo Clinic and Mayo College of Medicine Rochester, MN, 55905, USA
                [37 ]Department of Surgery, University of Medicine and Pharmacy ‘Gr T Popa’, Department of Surgical Oncology, Regional Institute of Oncology Iaşi, Romania
                [38 ]Medical Oncology and Innovative Therapies Unit, Istituto Nazionale per lo Studio e la Cura dei Tumouri, Fondazione ‘G Pascale’ Napoli, Italy
                [39 ]Research Branch, Sidra Medical and Research Centre Doha, Qatar
                [40 ]Laboratory of Molecular and Tumour Immunology, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center Portland, OR, USA
                [41 ]Department of Molecular Microbiology and Immunology, Oregon Health and Science University Portland, OR, USA
                [42 ]Immunomonitoring Platform, Laboratory of Immunology, Georges Pompidou European Hospital Paris, France
                Author notes
                Correspondence to: Jérôme Galon, INSERM, U872, Laboratory of Integrative Cancer Immunology, Cordeliers Research Centre, 15 Rue de l'Ecole de Médecine, 75006 Paris, France. e-mail: jerome.galon@ 123456crc.jussieu.fr
                Article
                10.1002/path.4287
                4255306
                24122236
                906e9f5e-80da-45c0-ba90-0ad0cd86d8d1
                © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 12 August 2013
                : 25 September 2013
                : 26 September 2013
                Categories
                Invited Reviews

                Pathology
                immunoscore,colorectal cancer,colon carcinoma,tumour microenvironment,immune response,classification,prognostic markers,predictive markers,t cells

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