title: TGF-beta modulates the functionality of tumor-infiltrating CD8+ T cells through effects on TCR signaling and Spred1 expression.
abstract: This study demonstrates that CD8+ T cells in the tumor microenvironment display reduced functionality and hyporesponsiveness. TGF-beta contributed markedly to the tumor-infiltrating CD8+ T cells' (TILs) reduced functionality, which could be reversed using a small molecule TGF-beta 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-beta 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-beta activity. Spred-1 was upregulated in CD8+ TILs and TGF-beta 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-beta 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.
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, MSC 1750, Bethesda, MD 20892, USA.
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: di Bari
authors.forename: M E Christine
authors.initials: ME
authors.lastname: Lutsiak
authors.forename: Shinji
authors.initials: S
authors.lastname: Takai
authors.forename: Sven
authors.initials: S
authors.lastname: Mostböck
authors.forename: Benedetto
authors.initials: B
authors.lastname: Farsaci
authors.forename: Roshanak Tolouei
authors.initials: RT
authors.lastname: Semnani
authors.forename: Lalage M
authors.initials: LM
authors.lastname: Wakefield
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schlom
authors.forename: Helen
authors.initials: H
authors.lastname: Sabzevari