title: Impaired functional responses in follicular lymphoma CD8+TIM-3+T lymphocytes following TCR engagement.
abstract: Upregulation of T cell immunoglobulin-3 (TIM-3) has been associated with negative regulation of the immune response in chronic infection and cancer, including lymphoma. Here, we investigated the possible correlation between TIM-3 expression byex vivocytotoxic T cells (CTL) from follicular lymphoma (FL) biopsies and their functional unresponsiveness that could limit the favorable impact of CTL on disease progression. We report a high percentage of CD8+TIM-3+T cells in lymph nodes of FL patients. When compared to their CD8+TIM-3-counterparts, CD8+TIM-3+T cells exhibited defective cytokine production following TCR engagement. Furthermore, CD8+TIM-3+T cells displayex vivomarkers of lytic granule release and remain unresponsive to further TCR-induced activation of the lytic machinery. Although confocal microscopy showed that TIM-3 expression on CD8+T cells correlated with minor alterations of immunological synapse, a selective reduction of ERK signaling in CD8+TIM-3+T cells was observed by phospho-flow analysis. Finally, short relapse-free survival despite rituximab(R)-chemotherapy was observed in patients with high content of TIM-3+cells and a poor infiltrate of granzyme B+T cells in FL lymph nodes. Together, our data indicate that, besides selective TCR early signaling defects, TIM-3 expression correlates with unresponsiveness ofex vivoCD8+T cells in FL. They show that scores based on the combination of exhaustion and cytolytic markers in FL microenvironment might be instrumental to identify patients at early risk of relapses following R-chemotherapy.
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, INSERM U1043, Toulouse, France; Département de Pathologie, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse, France; Laboratoire d'Excellence "TOUCAN," Toulouse, France; Program Hospitalo-Universitaire en Cancérologie "CAPTOR," Toulouse, France; CALYM Carnot Institute, Pierre-Bénite, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Gravelle
authors.affiliation: Institute for Cancer Genetics, Columbia University , New York, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Do
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, INSERM U1043, Toulouse, France; Département de Pathologie, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Franchet
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, INSERM U1043, Toulouse, France; Laboratoire d'Excellence "TOUCAN," Toulouse, France.
authors.forename: Sabina
authors.initials: S
authors.lastname: Mueller
authors.affiliation: Program Hospitalo-Universitaire en Cancérologie "CAPTOR," Toulouse, France; Département d'Hématologie, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Oberic
authors.affiliation: Laboratoire d'Excellence "TOUCAN," Toulouse, France; Program Hospitalo-Universitaire en Cancérologie "CAPTOR," Toulouse, France; CALYM Carnot Institute, Pierre-Bénite, France; Université Toulouse III Paul-Sabatier, Toulouse, France; Département d'Hématologie, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse, France; Centre de Recherches en Cancérologie de Toulouse, INSERM UMR1037, Toulouse, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: Ysebaert
authors.affiliation: Istituto di Anatomia Patologica, Università Cattolica del Sacro Cuore , Roma, Italy.
authors.forename: Luigi Maria
authors.initials: LM
authors.lastname: Larocca
authors.affiliation: Istituto di Ematologia, Università Cattolica del Sacro Cuore , Roma, Italy.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hohaus
authors.affiliation: Département d'ORL, Center Hospitalier Universitaire Purpan , Toulouse, France.
authors.forename: Marie-Noëlle
authors.initials: MN
authors.lastname: Calmels
authors.affiliation: Département de Pathologie, Institut Universitaire du Cancer-Oncopole de Toulouse , Toulouse, France.
authors.forename: François-Xavier
authors.identifier: 0000-0002-8433-7764
authors.initials: FX
authors.lastname: Frenois
authors.affiliation: Center for Lymphoid Cancer, BC Cancer Agency , Vancouver, BC, Canada.
authors.forename: Robert
authors.identifier: 0000-0003-0287-7124
authors.initials: R
authors.lastname: Kridel
authors.affiliation: Center for Lymphoid Cancer, BC Cancer Agency , Vancouver, BC, Canada.
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.affiliation: Laboratoire d'Excellence "TOUCAN," Toulouse, France; Program Hospitalo-Universitaire en Cancérologie "CAPTOR," Toulouse, France; CALYM Carnot Institute, Pierre-Bénite, France; Université Toulouse III Paul-Sabatier, Toulouse, France; Département d'Hématologie, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse, France; Centre de Recherches en Cancérologie de Toulouse, INSERM UMR1037, Toulouse, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Laurent
authors.affiliation: Département de Pathologie, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse, France; Laboratoire d'Excellence "TOUCAN," Toulouse, France; Program Hospitalo-Universitaire en Cancérologie "CAPTOR," Toulouse, France; CALYM Carnot Institute, Pierre-Bénite, France; Université Toulouse III Paul-Sabatier, Toulouse, France; Centre de Recherches en Cancérologie de Toulouse, INSERM UMR1037, Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Brousset
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, INSERM U1043, Toulouse, France; Département de Pathologie, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse, France; Laboratoire d'Excellence "TOUCAN," Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Valitutti
authors.affiliation: Centre de Physiopathologie de Toulouse Purpan, INSERM U1043, Toulouse, France; Département de Pathologie, Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse, France; Laboratoire d'Excellence "TOUCAN," Toulouse, France; Program Hospitalo-Universitaire en Cancérologie "CAPTOR," Toulouse, France; CALYM Carnot Institute, Pierre-Bénite, France; Université Toulouse III Paul-Sabatier, Toulouse, France; Centre de Recherches en Cancérologie de Toulouse, INSERM UMR1037, Toulouse, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Laurent
keywords: CD8+ T cell dysfunction; T cell exhaustion; TCR signaling impairment; TIM-3 immune-checkpoint; follicular lymphoma; immunological synapse; prognostic value