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

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.