Early T cell signalling is reversibly altered in PD-1+ T lymphocytes infiltrating human tumors

Shu Fang Wang, Stéphane Fouquet, Maxime Chapon, Hélène Salmon, Fabienne Regnier, Karine Labroquère, Cécile Badoual, Diane Damotte, Pierre Validire, Eve Maubec, Nicolas B. Delongchamps, Aurélie Cazes, Laure Gibault, Marylène Garcette, Marie Caroline Dieu-Nosjean, Marc Zerbib, Marie Françoise Avril, Armelle Prévost-Blondel, Clotilde Randriamampita, Alain TrautmannNadège Bercovici

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74 Scopus citations


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.

Original languageEnglish
Article numbere17621
JournalPLoS ONE
Issue number3
StatePublished - 2011
Externally publishedYes


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