PURPOSE: The purpose of this study was to evaluate the prognostic value of Immunoscore in patients with stage III colon cancer (CC) and to analyze its association with the effect of chemotherapy on time to recurrence (TTR). METHODS: An international study led by the Society for Immunotherapy of Cancer evaluated the predefined consensus Immunoscore in 763 patients with American Joint Committee on Cancer/Union for International Cancer Control TNM stage III CC from cohort 1 (Canada/United States) and cohort 2 (Europe/Asia). CD3+ and cytotoxic CD8+ T lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The primary end point was TTR. Secondary end points were overall survival (OS), disease-free survival (DFS), prognosis in microsatellite stable (MSS) status, and predictive value of efficacy of chemotherapy. RESULTS: Patients with a high Immunoscore presented with the lowest risk of recurrence, in both cohorts. Recurrence-free rates at 3 years were 56.9% (95% CI, 50.3% to 64.4%), 65.9% (95% CI, 60.8% to 71.4%), and 76.4% (95% CI, 69.3% to 84.3%) in patients with low, intermediate, and high immunoscores, respectively (hazard ratio [HR; high v low], 0.48; 95% CI, 0.32 to 0.71; P = .0003). Patients with high Immunoscore showed significant association with prolonged TTR, OS, and DFS (all P < .001). In Cox multivariable analysis stratified by participating center, Immunoscore association with TTR was independent (HR [high v low], 0.41; 95% CI, 0.25 to 0.67; P = .0003) of patient's sex, T stage, N stage, sidedness, and microsatellite instability status. Significant association of a high Immunoscore with prolonged TTR was also found among MSS patients (HR [high v low], 0.36; 95% CI, 0.21 to 0.62; P = .0003). Immunoscore had the strongest contribution χ2 proportion for influencing survival (TTR and OS). Chemotherapy was significantly associated with survival in the high-Immunoscore group for both low-risk (HR [chemotherapy v no chemotherapy], 0.42; 95% CI, 0.25 to 0.71; P = .0011) and high-risk (HR [chemotherapy v no chemotherapy], 0.5; 95% CI, 0.33 to 0.77; P = .0015) patients, in contrast to the low-Immunoscore group (P > .12). CONCLUSION: This study shows that a high Immunoscore significantly associated with prolonged survival in stage III CC. Our findings suggest that patients with a high Immunoscore will benefit the most from chemotherapy in terms of recurrence risk.

Center for Immuno Oncology University Hospital Siena Italy

Centre de Recherche des Cordeliers Sorbonne Université Sorbonne Paris Cité Université de Paris Paris France

Colorectal Surgery Department Istituto Nazionale Tumori IRCCS Fondazione G Pascale Napoli Italy

Curandis Laboratories Boston MA

Department of Biostatistics University of Texas MD Anderson Cancer Center Houston TX

Department of Gastroenterological Breast and Endocrine Surgery Yamaguchi University Graduate School of Medicine Yamaguchi Japan

Department of Immunology and Immunotherapy Kurume University School of Medicine Kurume Japan

Department of Immunology and Inflammation Humanitas Clinical and Research Center Rozzano Milan Italy and Humanitas University Rozzano Milan Italy

Department of Laboratory Medicine and Pathobiology University of Toronto Toronto Ontario Canada

Department of Medical Oncology University Hospital of Bern Bern Switzerland

Department of Medicine and Surgery University of Parma and Laboratory of Molecular Gastroenterology Humanitas Clinical and Research Center Rozzano Milan Italy

Department of Molecular Microbiology and Immunology Oregon Health and Science University Portland OR

Department of Oncology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Oncology Pathology Karolinska Institutet Karolinska University Stockholm Sweden

Department of Pathology and Laboratory Medicine University Health Network Toronto Ontario Canada

Department of Pathology AP HP Assistance Publique Hopitaux de Paris Georges Pompidou European Hospital Paris France

Department of Pathology Cliniques Universitaires St Luc and Institut de Recherche Clinique et Experimentale Université Catholique de Louvain Brussels Belgium

Department of Pathology Istituto Nazionale Tumori IRCCS Fondazione G Pascale Napoli Italy

Department of Pathology Memorial Sloan Kettering Cancer Center New York NY

Department of Pathology Providence Portland Medical Center Portland OR

Department of Pathology Radboud Institute of Molecular Life Sciences Radboudumc Nijmegen The Netherlands

Department of Pathology Sapporo Medical University School of Medicine Sapporo Japan

Department of Pathology University Hospital Erlangen Friedrich Alexander Universität Erlangen Nürnberg Erlangen Germany

Department of Surgery Kindai University School of Medicine Osaka sayama Japan

Department of Surgery Surgical Oncology and Science Sapporo Medical University School of Medicine Sapporo Japan

Department of Surgery University Hospital Erlangen Friedrich Alexander Universität Erlangen Nürnberg Erlangen Germany

Department of Translational Research and Developmental Therapeutics against Cancer Yamaguchi University School of Medicine Yamaguchi Japan

Digestive Surgery Department AP HP Assistance Publique Hopitaux de Paris Georges Pompidou European Hospital Paris France

Division of Cellular Signaling Institute for Advanced Medical Research Keio University School of Medicine Tokyo Japan

Equipe Labellisée Ligue Contre le Cancer Paris France

Immunomonitoring Platform Laboratory of Immunology AP HP Assistance Publique Hopitaux de Paris Georges Pompidou European Hospital Paris France

Inovarion Paris France

INSERM Laboratory of Integrative Cancer Immunology Paris France

Institut Roi Albert 2 Department of Digestive Surgery Cliniques Universitaires St Luc Université Catholique de Louvain Brussels Belgium

Institut Roi Albert 2 Department of Medical Oncology Cliniques Universitaires St Luc and Institut de Recherche Clinique et Experimentale Université Catholique de Louvain Brussels Belgium

Institute of Cancer Research Center of Translational Medicine Health Science Center of Xi'an Jiaotong University Xian China

Institute of Pathology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Institute of Pathology University of Bern Bern Switzerland

IRCCS Istituto Nazionale Tumori Regina Elena Rome Italy

Laboratory of Molecular and Tumor Immunology Earle A Chiles Research Institute Robert W Franz Cancer Center Providence Portland Medical Center Portland OR

Melanoma Cancer Immunotherapy and Innovative Therapies Unit Istituto Nazionale Tumori IRCCS Fondazione G Pascale Napoli Italy

Princess Margaret Cancer Centre UHN Toronto Ontario Canada

Refuge Biotechnologies Menlo Park CA

The Gujarat Cancer and Research Institute Asarwa Ahmedabad India

University of Medicine and Pharmacy Grigore T Popa Iaşi Department of Surgical Oncology Regional Institute of Oncology Iaşi Romania

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Multi-Institutional Evaluation of Pathologists' Assessment Compared to Immunoscore

Multicenter International Study of the Consensus Immunoscore for the Prediction of Relapse and Survival in Early-Stage Colon Cancer

Clinical Performance of the Consensus Immunoscore in Colon Cancer in the Asian Population from the Multicenter International SITC Study