title: Early T cell signalling is reversibly altered in PD-1+ T lymphocytes infiltrating human tumors.
abstract: To improve cancer immunotherapy, a better understanding of the weak efficiency of tumor-infiltrating T lymphocytes (TIL) is necessary. We have analyzed the functional state of human TIL immediately after resection of three types of tumors (NSCLC, melanoma and RCC). Several signalling pathways (calcium, phosphorylation of ERK and Akt) and cytokine secretion are affected to different extents in TIL, and show a partial spontaneous recovery within a few hours in culture. The global result is an anergy that is quite distinct from clonal anergy induced in vitro, and closer to adaptive tolerance in mice. PD-1 (programmed death -1) is systematically expressed by TIL and may contribute to their anergy by its mere expression, and not only when it interacts with its ligands PD-L1 or PD-L2, which are not expressed by every tumor. Indeed, the TCR-induced calcium and ERK responses were reduced in peripheral blood T cells transfected with PD-1. Inhibition by sodium stibogluconate of the SHP-1 and SHP-2 phosphatases that associate with several inhibitory receptors including PD-1, relieves part of the anergy apparent in TIL or in PD-1-transfected T cells. This work highlights some of the molecular modifications contributing to functional defects of human TIL.
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France.
authors.forename: Shu-Fang
authors.initials: SF
authors.lastname: Wang
authors.forename: Stéphane
authors.initials: S
authors.lastname: Fouquet
authors.forename: Maxime
authors.initials: M
authors.lastname: Chapon
authors.forename: Hélène
authors.initials: H
authors.lastname: Salmon
authors.forename: Fabienne
authors.initials: F
authors.lastname: Regnier
authors.forename: Karine
authors.initials: K
authors.lastname: Labroquère
authors.forename: Cécile
authors.initials: C
authors.lastname: Badoual
authors.forename: Diane
authors.initials: D
authors.lastname: Damotte
authors.forename: Pierre
authors.initials: P
authors.lastname: Validire
authors.forename: Eve
authors.initials: E
authors.lastname: Maubec
authors.forename: Nicolas B
authors.initials: NB
authors.lastname: Delongchamps
authors.forename: Aurélie
authors.initials: A
authors.lastname: Cazes
authors.forename: Laure
authors.initials: L
authors.lastname: Gibault
authors.forename: Marylène
authors.initials: M
authors.lastname: Garcette
authors.forename: Marie-Caroline
authors.initials: MC
authors.lastname: Dieu-Nosjean
authors.forename: Marc
authors.initials: M
authors.lastname: Zerbib
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Avril
authors.forename: Armelle
authors.initials: A
authors.lastname: Prévost-Blondel
authors.forename: Clotilde
authors.initials: C
authors.lastname: Randriamampita
authors.forename: Alain
authors.initials: A
authors.lastname: Trautmann
authors.forename: Nadège
authors.initials: N
authors.lastname: Bercovici
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D000967:Antimony Sodium Gluconate / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001706:Biopsy; D002118:Calcium / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D017635:Clonal Anergy / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology*; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D009369:Neoplasms / Q000276:immunology / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D008024:Ligands; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D002118:Calcium; D000967:Antimony Sodium Gluconate