• Laetitia Marisa, Magali Svrcek, Ada Collura, Etienne Becht, Pascale Cervera, Kristell Wanherdrick, Olivier Buhard, Anastasia Goloudina, Vincent Jonchère, Janick Selves, Gerard Milano, Dominique Guenot, Romain Cohen, Chrystelle Colas, Pierre Laurent-Puig, Sylviane Olschwang, Jérémie H Lefèvre, Yann Parc, Valérie Boige, Côme Lepage, Thierry André, Jean-François Fléjou, Valentin Dérangère, François Ghiringhelli, Aurélien de Reynies, and Alex Duval.
• Programme "Cartes d'Identité des Tumeurs," Ligue Nationale Contre le Cancer, Paris, France; INSERM, UMRS 938 - Centre de Recherche Saint-Antoine, Equipe "Instabilité des Microsatellites et Cancers," Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France; Sorbonne Université, UPMC Univ Paris 06, Paris, France; AP-HP, Hôpital Saint-Antoine, Service d'Anatomie et Cytologie Pathologiques, Paris, France; Centre de Recherche en Cancérologie de Toulouse, UMR 1037 INSERM - Université Toulouse III, Department of Pathology, CHU, Toulouse, France; Laboratoire d'Oncopharmacologie, EA 3836, Centre Antoine Lacassagne, Nice, France; INSERM, U682, Développement et Physiopathologie de l'Intestin et du Pancréas, Strasbourg, France; AP-HP, Hôpital Saint-Antoine, Service d'Oncologie Médicale, Paris, France; AP-HP, Laboratoire d'oncogénétique et d'Angiogénétique, GH Pitié-Salpétrière, Paris, France; INSERM, Unité Mixte de Recherche, Paris Sorbonne Cité, Université Paris Descartes, Paris, France; Aix Marseille Univ, INSERM, GMGF, Marseille, France and RGDS, HP Clairval, Marseille, France; AP-HP, Service de Chirurgie Générale et Digestive, Hôpital Saint-Antoine, Paris, France; Department of Oncologic Medicine, Gustave-Roussy, Villejuif, France; Université Paris Descartes, Paris Sorbonne Cité INSERM UMR-S775, Paris, France; INSERM, Burgundy Cancer Registry, U866, Burgundy University, Dijon University Hospital, BP 87900?21079 Dijon, France; Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, France; INSERM, UMR866, Burgundy University; Platform of transfer in oncology, Burgundy University, Centre Georges-François Leclerc, Dijon, France.
• J. Natl. Cancer Inst. 2018 Jan 1; 110 (1).

BackgroundImmune checkpoint (ICK) expression might represent a surrogate measure of tumor-infiltrating T cell (CTL) exhaustion and therefore be a more accurate prognostic biomarker for colorectal cancer (CRC) patients than CTL enumeration as measured by the Immunoscore.MethodsThe expression of ICKs, Th1, CTLs, cytotoxicity-related genes, and metagenes, including Immunoscore-like metagenes, were evaluated in three independent cohorts of CRC samples (260 microsatellite instable [MSI], 971 non-MSI). Their associations with patient survival were analyzed by Cox models, taking into account the microsatellite instability (MSI) status and affiliation with various Consensus Molecular Subgroups (CMS). PD-L1 and CD8 expression were examined on a subset of tumors with immunohistochemistry. All statistical tests were two-sided.ResultsThe expression of Immunoscore-like metagenes was statistically significantly associated with improved outcome in non-MSI tumors displaying low levels of both CTLs and immune checkpoints (ICKs; CMS2 and CMS3; hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.43 to 0.92, P = .02; and HR = 0.55, 95% CI = 0.34 to 0.90, P = .02, respectively), but clearly had no prognostic relevance in CRCs displaying higher levels of CTLs and ICKs (CMS1 and CMS4; HR = 0.46, 95% CI = 0.10 to 2.10, P = .32; and HR = 1.13, 95% CI = 0.79 to 1.63, P = .50, respectively), including MSI tumors. ICK metagene expression was statistically significantly associated with worse prognosis independent of tumor staging in MSI tumors (HR = 3.46, 95% CI = 1.41 to 8.49, P = .007). ICK expression had a negative impact on the proliferation of infiltrating CD8 T cells in MSI neoplasms (median = 0.56 in ICK low vs median = 0.34 in ICK high, P = .004).ConclusionsICK expression cancels the prognostic relevance of CTLs in highly immunogenic colon tumors and predicts a poor outcome in MSI CRC patients.© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

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