Cancer Immunology, Immunotherapy

, Volume 58, Issue 11, pp 1809–1818 | Cite as

TGF-β modulates the functionality of tumor-infiltrating CD8+ T cells through effects on TCR signaling and Spred1 expression

  • Maria Giovanna di Bari
  • M. E. Christine Lutsiak
  • Shinji Takai
  • Sven Mostböck
  • Benedetto Farsaci
  • Roshanak Tolouei Semnani
  • Lalage M. Wakefield
  • Jeffrey Schlom
  • Helen Sabzevari
Original article

Abstract

This study demonstrates that CD8+ T cells in the tumor microenvironment display reduced functionality and hyporesponsiveness. TGF-β contributed markedly to the tumor-infiltrating CD8+ T cells’ (TILs) reduced functionality, which could be reversed using a small molecule TGF-β inhibitor. Upon T-cell receptor (TCR) activation, the activation of ITK and ERK kinases were reduced in CD8+ TILs, as compared to splenic CD8+ T cells: TGF-β inhibitor could reverse this phenomenon. This study demonstrates for the first time the association of the Spred-1 gene, an inhibitor of the Ras/MAPK pathway, with CD8+ TILs and TGF-β activity. Spred-1 was upregulated in CD8+ TILs and TGF-β enhanced the expression of Spred-1 in effector/memory CD8+ T cells and not in rested/memory CD8+ T cells. Based on these findings, this study supports the hypothesis that TGF-β mediates an inhibitory mechanism on CD8+ TILs involving TCR-signaling blockade and the upregulation of Spred-1, thus implicating Spred-1 as a potential new target for future anti-tumor immune studies.

Keywords

T cells Tolerance/suppression/anergy Tumor immunity Signal transduction 

Supplementary material

262_2009_692_MOESM1_ESM.doc (1.1 mb)
Supplementary material (DOC 1085 kb)

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Maria Giovanna di Bari
    • 1
  • M. E. Christine Lutsiak
    • 1
  • Shinji Takai
    • 1
  • Sven Mostböck
    • 1
  • Benedetto Farsaci
    • 1
  • Roshanak Tolouei Semnani
    • 2
  • Lalage M. Wakefield
    • 3
  • Jeffrey Schlom
    • 1
  • Helen Sabzevari
    • 1
  1. 1.Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute National Institutes of HealthBethesdaUSA
  2. 2.Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases National Institutes of HealthBethesdaUSA
  3. 3.Laboratory of Cancer Biology and Genetics, National Cancer Institute National Institutes of HealthBethesdaUSA

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