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

PLoS One. 2011 Mar 7;6(3):e17621. doi: 10.1371/journal.pone.0017621.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / metabolism*
  • Antimony Sodium Gluconate / pharmacology
  • Apoptosis Regulatory Proteins / metabolism*
  • Biopsy
  • Calcium / metabolism
  • Cell Communication / drug effects
  • Cell Communication / immunology
  • Clonal Anergy / drug effects
  • Humans
  • Ligands
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Myeloid Cells / drug effects
  • Myeloid Cells / immunology
  • Myeloid Cells / pathology
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Programmed Cell Death 1 Receptor
  • Signal Transduction / drug effects
  • Signal Transduction / immunology*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology


  • Antigens, CD
  • Apoptosis Regulatory Proteins
  • Ligands
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Calcium
  • Antimony Sodium Gluconate