Regulatory T cells suppress the cytotoxic phenotype of T cells in intestinal tumors of APCMin/+ mice

Abstract

Abstract The presence of activated T cells in colorectal cancer (CRC) tissues is a strong predictor of patient survival. Our previous research have shown that regulatory T cells (Treg) are able to reduce T-cell transendothelial migration in vitro and accumulation of effector T cells in intestinal tumors in vivo in a murine model for intestinal adenomas (APCMin/+). In this study we investigated the effect of Treg depletion on the cytotoxic potential of conventional αβ T cells and γδ T cells in intestinal adenomas. We used the APCMin/+ \DEREG mouse model, which harbours a high affinity diphtheria toxin receptor under the control of the FOXP3 promoter, to deplete Treg in tumor bearing mice. We found that the number of CD8αβ T cells per mg tissue in the lamina propria was significantly increased in the Treg depleted intestinal adenomas in comparison to the non-depleted tumors. We could confirm this finding with IHC staining in tissue sections. The number of CD8αα T cells and γδ T cells remained unchanged. Furthermore, ex vivo frequencies in the lamina propria of Granzyme B+ CD8αβ T cells were increased in the Treg depleted intestinal adenomas. Following in vitro stimulation of lymphocytes from lamina propria with PMA/ionomycin, there was a trend towards a higher frequency of IFNγ+ CD8αβ T cells in Treg depleted adenomas, but frequencies of CD107a+ CD8αβ T cells were decreased. The frequency of TNF+CD8αβ T cells was elevated in the tumor in comparison to the unaffected tissue regardless of Treg depletion. We are investigating the combined effect of Treg depletion and PD-1 immunotherapy on the cytotoxic phenotype of T cells in the intestinal adenomas. The results indicate that the modulation of Treg in colorectal cancer could have apositive effect on T cell cytotoxicity.