title: Tim-3 Expression on Tumor-Infiltrating PD-1+CD8+T Cells Correlates with Poor Clinical Outcome in Renal Cell Carcinoma.
abstract: Inhibitory receptors expressed by T cells mediate tolerance to tumor antigens, with coexpression of these receptors exacerbating this dysfunctional state. Using the VectraR automated multiparametric immunofluorescence technique, we quantified intratumoral CD8+T cells coexpressing the inhibitory receptors PD-1 and Tim-3 from patients with renal cell carcinoma (RCC). A second validation cohort measured the same parameters by cytometry. The percentage of tumor-infiltrating CD8+T cells coexpressing PD-1 and Tim-3 correlated with an aggressive phenotype and a larger tumor size at diagnosis. Coexpression of PD-1 and Tim-3 above the median conferred a higher risk of relapse and a poorer 36-month overall survival. Notably, other CD8+T-cell subsets did not exert a similar effect on overall survival. Moreover, only the PD-1+Tim-3+subset of CD8+T cells exhibited impaired function after stimulation. Our findings establish intratumoral Tim-3+PD1+CD8+T cells as critical mediators of an aggressive phenotype in RCC. Use of the Vectra tool may be useful to identify similarly critical prognostic and predictive biomarkers in other tumor types and their response to immunotherapy.Cancer Res; 77(5); 1075-82. ©2016 AACR.
authors.affiliation: INSERM U970, Université Paris Descartes, Sorbonne Paris-Cité, Paris, France.
authors.forename: Clémence
authors.initials: C
authors.lastname: Granier
authors.affiliation: INSERM U970, Université Paris Descartes, Sorbonne Paris-Cité, Paris, France.|Department of Urology, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Dariane
authors.affiliation: INSERM U970, Université Paris Descartes, Sorbonne Paris-Cité, Paris, France.|Service d'Oncologie Médicale, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Combe
authors.affiliation: Department of Pathology, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Verkarre
authors.affiliation: EA08: Evaluation des Thérapeutiques et Pharmacologie Périnatale et Pédiatrique, Unité de Recherche Clinique Paris Centre, Paris, France.|CIC 1419 INSERM Cochin-Necker, Paris, France.
authors.forename: Saïk
authors.initials: S
authors.lastname: Urien
authors.affiliation: INSERM U970, Université Paris Descartes, Sorbonne Paris-Cité, Paris, France.|Department of Pathology, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Badoual
authors.affiliation: INSERM U970, Université Paris Descartes, Sorbonne Paris-Cité, Paris, France.|Department of Pathology, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Roussel
authors.affiliation: INSERM U970, Université Paris Descartes, Sorbonne Paris-Cité, Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Mandavit
authors.affiliation: CNRS UMR5048 Centre de Biochimie Structurale, INSERM U554, Université de Montpellier 1 et 2, Montpellier, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Ravel
authors.affiliation: Department of Pathology, Hôpital Cochin, Paris, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Sibony
authors.affiliation: Université Paris Diderot Paris 7, Paris, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Biard
authors.affiliation: Department of Pathology, Hôpital Foch, Suresnes, France.
authors.forename: Camélia
authors.initials: C
authors.lastname: Radulescu
authors.affiliation: INSERM U970, Université Paris Descartes, Sorbonne Paris-Cité, Paris, France.|Service d'Immunologie Biologique, AP-HP, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Emeline
authors.initials: E
authors.lastname: Vinatier
authors.affiliation: INSERM U970, Université Paris Descartes, Sorbonne Paris-Cité, Paris, France.|Service d'Immunologie Biologique, AP-HP, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Benhamouda
authors.affiliation: Department of Urology, Hôpital Cochin, Paris, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Peyromaure
authors.affiliation: INSERM U970, Université Paris Descartes, Sorbonne Paris-Cité, Paris, France.|Service d'Oncologie Médicale, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Oudard
authors.affiliation: Department of Urology, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Méjean
authors.affiliation: Department of Urology, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Marc-Olivier
authors.initials: MO
authors.lastname: Timsit
authors.affiliation: INSERM U970, Université Paris Descartes, Sorbonne Paris-Cité, Paris, France.|Service d'Immunologie Biologique, AP-HP, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Gey
authors.affiliation: INSERM U970, Université Paris Descartes, Sorbonne Paris-Cité, Paris, France. eric.tartour@aphp.fr.|Service d'Immunologie Biologique, AP-HP, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Tartour
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000473:pathology; D015331:Cohort Studies; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000096:biosynthesis* / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D007680:Kidney Neoplasms / Q000276:immunology* / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*; D012189:Retrospective Studies; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor