Franck Pagès1, Bernhard Mlecnik2, Florence Marliot3, Gabriela Bindea4, Fang-Shu Ou5, Carlo Bifulco6, Alessandro Lugli7, Inti Zlobec7, Tilman T Rau7, Martin D Berger8, Iris D Nagtegaal9, Elisa Vink-Börger9, Arndt Hartmann10, Carol Geppert10, Julie Kolwelter10, Susanne Merkel11, Robert Grützmann11, Marc Van den Eynde12, Anne Jouret-Mourin13, Alex Kartheuser14, Daniel Léonard14, Christophe Remue14, Julia Y Wang15, Prashant Bavi16, Michael H A Roehrl17, Pamela S Ohashi18, Linh T Nguyen18, SeongJun Han18, Heather L MacGregor18, Sara Hafezi-Bakhtiari19, Bradly G Wouters18, Giuseppe V Masucci20, Emilia K Andersson20, Eva Zavadova21, Michal Vocka21, Jan Spacek21, Lubos Petruzelka21, Bohuslav Konopasek21, Pavel Dundr22, Helena Skalova22, Kristyna Nemejcova22, Gerardo Botti23, Fabiana Tatangelo23, Paolo Delrio24, Gennaro Ciliberto25, Michele Maio26, Luigi Laghi27, Fabio Grizzi28, Tessa Fredriksen4, Bénédicte Buttard4, Mihaela Angelova4, Angela Vasaturo4, Pauline Maby4, Sarah E Church29, Helen K Angell30, Lucie Lafontaine4, Daniela Bruni4, Carine El Sissy3, Nacilla Haicheur31, Amos Kirilovsky3, Anne Berger32, Christine Lagorce32, Jeffrey P Meyers5, Christopher Paustian33, Zipei Feng33, Carmen Ballesteros-Merino33, Jeroen Dijkstra9, Carlijn van de Water9, Shannon van Lent-van Vliet9, Nikki Knijn9, Ana-Maria Mușină34, Dragos-Viorel Scripcariu34, Boryana Popivanova35, Mingli Xu35, Tomonobu Fujita35, Shoichi Hazama36, Nobuaki Suzuki37, Hiroaki Nagano37, Kiyotaka Okuno38, Toshihiko Torigoe39, Noriyuki Sato39, Tomohisa Furuhata40, Ichiro Takemasa40, Kyogo Itoh41, Prabhu S Patel42, Hemangini H Vora42, Birva Shah42, Jayendrakumar B Patel42, Kruti N Rajvik42, Shashank J Pandya42, Shilin N Shukla42, Yili Wang43, Guanjun Zhang43, Yutaka Kawakami35, Francesco M Marincola44, Paolo A Ascierto45, Daniel J Sargent5, Bernard A Fox46, Jérôme Galon47. 1. INSERM, Laboratory of Integrative Cancer Immunology, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Sorbonne Universités, Paris, France; Immunomonitoring Platform, Laboratory of Immunology, AP-HP, Assistance Publique-Hopitaux de Paris, Georges Pompidou European Hospital, Paris, France. Electronic address: franck.pages@aphp.fr. 2. INSERM, Laboratory of Integrative Cancer Immunology, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Sorbonne Universités, Paris, France; Inovarion, Paris, France. 3. INSERM, Laboratory of Integrative Cancer Immunology, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Sorbonne Universités, Paris, France; Immunomonitoring Platform, Laboratory of Immunology, AP-HP, Assistance Publique-Hopitaux de Paris, Georges Pompidou European Hospital, Paris, France. 4. INSERM, Laboratory of Integrative Cancer Immunology, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Sorbonne Universités, Paris, France. 5. Cancer Center Statistics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA. 6. Department of Pathology, Providence Portland Medical Center, Portland, OR, USA. 7. Institute of Pathology, University of Bern, Bern, Switzerland. 8. Department of Medical Oncology, University Hospital of Bern, Bern, Switzerland. 9. Pathology Department, Radboud University, Nijmegen, Netherlands. 10. Department of Pathology, University Erlangen-Nürnberg, Erlangen, Germany. 11. Department of Surgery, University Erlangen-Nürnberg, Erlangen, Germany. 12. Institut Roi Albert II, Department of Medical Oncology Cliniques Universitaires St-Luc, Brussels, Belgium; Institut de Recherche Clinique et Experimentale (Pole MIRO), Université Catholique de Louvain, Brussels, Belgium. 13. Department of Pathology, Cliniques Universitaires St-Luc, Brussels, Belgium; Institut de Recherche Clinique et Experimentale (Pole GAEN), Université Catholique de Louvain, Brussels, Belgium. 14. Institut Roi Albert II, Department of Digestive Surgery, Cliniques Universitaires St-Luc Université Catholique de Louvain, Brussels, Belgium. 15. Curandis Laboratories, Boston, MA, USA; Department of Pathology and Laboratory Medicine, University Health Network, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. 16. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. 17. Department of Pathology and Laboratory Medicine, University Health Network, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 18. University Health Network, Toronto, ON, Canada. 19. Department of Pathology and Laboratory Medicine, University Health Network, Toronto, ON, Canada. 20. Department of Oncology-Pathology, Karolinska Institutet, Karolinska University, Stockholm, Sweden. 21. Department of Oncology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic. 22. Institute of Pathology, First Faculty of Medicine, Charles University, Prague, Czech Republic; General University Hospital in Prague, Prague, Czech Republic. 23. Department of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G.Pascale" Naples, Italy. 24. Colorectal Surgery Department, Istituto Nazionale per lo Studio e la Cura dei Tumori, "Fondazione G.Pascale" Naples, Italy. 25. IRCCS Istituto Nazionale Tumori "Regina Elena", Rome, Italy. 26. Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy. 27. Molecular Gastroenterology and Department of Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. 28. Molecular Gastroenterology and Department of Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; Humanitas University, Rozzano, Milan, Italy. 29. INSERM, Laboratory of Integrative Cancer Immunology, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Sorbonne Universités, Paris, France; NanoString Technologies, Seattle, WA, USA. 30. INSERM, Laboratory of Integrative Cancer Immunology, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Sorbonne Universités, Paris, France; Translational Science, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK. 31. Immunomonitoring Platform, Laboratory of Immunology, AP-HP, Assistance Publique-Hopitaux de Paris, Georges Pompidou European Hospital, Paris, France. 32. INSERM, Laboratory of Integrative Cancer Immunology, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Sorbonne Universités, Paris, France; Digestive Surgery Department, AP-HP, Assistance Publique-Hopitaux de Paris, Georges Pompidou European Hospital, Paris, France. 33. Laboratory of Molecular and Tumor Immunology, Earle A. Chiles Research Institute, Robert W Franz Cancer Center, Providence Portland Medical Center, Portland, OR, USA. 34. University of Medicine and Pharmacy "Grigore T. Popa" Iaşi, Department of Surgical Oncology, Regional Institute of Oncology, Iaşi, Roumania. 35. Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan. 36. Department of Translational Research and Developmental Therapeutics against Cancer, Yamaguchi University School of Medicine, Yamaguchi, Japan. 37. Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan. 38. Department of Surgery, Kindai University, School of Medicine, Osaka-sayama, Japan. 39. Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan. 40. Department of Surgery, Surgical Oncology, and Science, Sapporo Medical University School of Medicine, Sapporo, Japan. 41. Department of Immunology and Immunotherapy, Kurume University School of Medicine, Kurume, Japan. 42. The Gujarat Cancer & Research Institute, Asarwa, Ahmedabad, India. 43. Institute for Cancer Research of School of Basic Medical Science, Department of Pathology of the First Affiliated Hospital, Health Science Center of Xi'an Jiaotong University, Xian, China. 44. Research Branch, Sidra Medical and Research Centre, Doha, Qatar. 45. Melanoma, Cancer Immunotherapy and Innovative Therapies Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "G. Pascale", Napoli, Italy. 46. Laboratory of Molecular and Tumor Immunology, Earle A. Chiles Research Institute, Robert W Franz Cancer Center, Providence Portland Medical Center, Portland, OR, USA; Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR, USA. 47. INSERM, Laboratory of Integrative Cancer Immunology, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, Sorbonne Universités, Paris, France. Electronic address: jerome.galon@crc.jussieu.fr.
Abstract
BACKGROUND: The estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I-III colon cancer. METHODS: An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I-III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology. An Immunoscore for each patient was derived from the mean of four density percentiles. The primary endpoint was to evaluate the prognostic value of the Immunoscore for time to recurrence, defined as time from surgery to disease recurrence. Stratified multivariable Cox models were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders. Harrell's C-statistics was used to assess model performance. FINDINGS: Tissue samples from 3539 patients were processed, and samples from 2681 patients were included in the analyses after quality controls (700 patients in the training set, 636 patients in the internal validation set, and 1345 patients in the external validation set). The Immunoscore assay showed a high level of reproducibility between observers and centres (r=0·97 for colon tumour; r=0·97 for invasive margin; p<0·0001). In the training set, patients with a high Immunoscore had the lowest risk of recurrence at 5 years (14 [8%] patients with a high Immunoscore vs 65 (19%) patients with an intermediate Immunoscore vs 51 (32%) patients with a low Immunoscore; hazard ratio [HR] for high vs low Immunoscore 0·20, 95% CI 0·10-0·38; p<0·0001). The findings were confirmed in the two validation sets (n=1981). In the stratified Cox multivariable analysis, the Immunoscore association with time to recurrence was independent of patient age, sex, T stage, N stage, microsatellite instability, and existing prognostic factors (p<0·0001). Of 1434 patients with stage II cancer, the difference in risk of recurrence at 5 years was significant (HR for high vs low Immunoscore 0·33, 95% CI 0·21-0·52; p<0·0001), including in Cox multivariable analysis (p<0·0001). Immunoscore had the highest relative contribution to the risk of all clinical parameters, including the American Joint Committee on Cancer and Union for International Cancer Control TNM classification system. INTERPRETATION: The Immunoscore provides a reliable estimate of the risk of recurrence in patients with colon cancer. These results support the implementation of the consensus Immunoscore as a new component of a TNM-Immune classification of cancer. FUNDING: French National Institute of Health and Medical Research, the LabEx Immuno-oncology, the Transcan ERAnet Immunoscore European project, Association pour la Recherche contre le Cancer, CARPEM, AP-HP, Institut National du Cancer, Italian Association for Cancer Research, national grants and the Society for Immunotherapy of Cancer.
BACKGROUND: The estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I-III colon cancer. METHODS: An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I-III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology. An Immunoscore for each patient was derived from the mean of four density percentiles. The primary endpoint was to evaluate the prognostic value of the Immunoscore for time to recurrence, defined as time from surgery to disease recurrence. Stratified multivariable Cox models were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders. Harrell's C-statistics was used to assess model performance. FINDINGS: Tissue samples from 3539 patients were processed, and samples from 2681 patients were included in the analyses after quality controls (700 patients in the training set, 636 patients in the internal validation set, and 1345 patients in the external validation set). The Immunoscore assay showed a high level of reproducibility between observers and centres (r=0·97 for colon tumour; r=0·97 for invasive margin; p<0·0001). In the training set, patients with a high Immunoscore had the lowest risk of recurrence at 5 years (14 [8%] patients with a high Immunoscore vs 65 (19%) patients with an intermediate Immunoscore vs 51 (32%) patients with a low Immunoscore; hazard ratio [HR] for high vs low Immunoscore 0·20, 95% CI 0·10-0·38; p<0·0001). The findings were confirmed in the two validation sets (n=1981). In the stratified Cox multivariable analysis, the Immunoscore association with time to recurrence was independent of patient age, sex, T stage, N stage, microsatellite instability, and existing prognostic factors (p<0·0001). Of 1434 patients with stage II cancer, the difference in risk of recurrence at 5 years was significant (HR for high vs low Immunoscore 0·33, 95% CI 0·21-0·52; p<0·0001), including in Cox multivariable analysis (p<0·0001). Immunoscore had the highest relative contribution to the risk of all clinical parameters, including the American Joint Committee on Cancer and Union for International Cancer Control TNM classification system. INTERPRETATION: The Immunoscore provides a reliable estimate of the risk of recurrence in patients with colon cancer. These results support the implementation of the consensus Immunoscore as a new component of a TNM-Immune classification of cancer. FUNDING: French National Institute of Health and Medical Research, the LabEx Immuno-oncology, the Transcan ERAnet Immunoscore European project, Association pour la Recherche contre le Cancer, CARPEM, AP-HP, Institut National du Cancer, Italian Association for Cancer Research, national grants and the Society for Immunotherapy of Cancer.
Authors: Siwen Hu-Lieskovan; Srabani Bhaumik; Kavita Dhodapkar; Jean-Charles J B Grivel; Sumati Gupta; Brent A Hanks; Sylvia Janetzki; Thomas O Kleen; Yoshinobu Koguchi; Amanda W Lund; Cristina Maccalli; Yolanda D Mahnke; Ruslan D Novosiadly; Senthamil R Selvan; Tasha Sims; Yingdong Zhao; Holden T Maecker Journal: J Immunother Cancer Date: 2020-12 Impact factor: 13.751
Authors: Tsuyoshi Hamada; Li Liu; Jonathan A Nowak; Kosuke Mima; Yin Cao; Kimmie Ng; Tyler S Twombly; Mingyang Song; Seungyoun Jung; Ruoxu Dou; Yohei Masugi; Keisuke Kosumi; Yan Shi; Annacarolina da Silva; Mancang Gu; Wanwan Li; NaNa Keum; Kana Wu; Katsuhiko Nosho; Kentaro Inamura; Jeffrey A Meyerhardt; Daniel Nevo; Molin Wang; Marios Giannakis; Andrew T Chan; Edward L Giovannucci; Charles S Fuchs; Reiko Nishihara; Xuehong Zhang; Shuji Ogino Journal: Eur J Cancer Date: 2018-09-13 Impact factor: 9.162
Authors: Tatiana Cunha Pereira; Paulo Rodrigues-Santos; Jani Sofia Almeida; Fábio Rêgo Salgueiro; Ana Raquel Monteiro; Filipa Macedo; Rita Félix Soares; Isabel Domingues; Paula Jacinto; Gabriela Sousa Journal: Med Oncol Date: 2021-03-31 Impact factor: 3.064
Authors: Valentina Thomas; Maura B Cotter; Miriam Tosetto; Yi Ling Khaw; Robert Geraghty; Desmond C Winter; Elizabeth J Ryan; Kieran Sheahan; Simon J Furney Journal: NPJ Genom Med Date: 2020-07-03 Impact factor: 8.617