The T-box transcription factor eomesodermin controls CD8 T cell activity and lymph node metastasis in human colorectal cancer

Abstract

Background/aims: An efficient cytolytic T cell function is essential for immune mediated rejection of colorectal cancer. However, the molecular mechanisms driving T cell mediated cancer rejection are still poorly understood. Here, we assessed the relevance of the T-box transcription factor eomesodermin in colorectal cancer. Methods/results: By analysing tissue probes from 88 different colorectal tumours, a significant (p,0.02) inverse correlation between eomesodermin expression in colorectal cancers and the presence of lymph node metastases could be shown, whereas no such correlation was noted for the master transcription factor of regulatory T cells, FoxP3 and CD8alpha expression. To evaluate whether this effect might be due to effects of eomesodermin on tumour infiltrating CD8 T cells, we subsequently analysed the regulated expression and function of this transcription factor in human T cells. Whereas overexpression of this factor induced perforin but not granzyme expression, siRNA mediated suppression of eomesodermin expression led to significantly reduced IFN-c production, perforin levels and cytolytic activity of CD8 T cells. Furthermore, TGF-b and IL4 could be identified as important inducer of eomesodermin expression. Conclusion: These data define for the first time a regulatory role of eomesodermin for CD8 T cell activity in humans. Our findings are consistent with a model in which eomesodermin expression in tumour infiltrating T cells regulates cytolytic functions of CD8 T cells via perforin expression. These data provide novel insights into control mechanisms governing the functional activity of human CD8 T lymphocytes via T-box transcription factors in cancer.

Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI

“…capacity determines the effectiveness of the immune system mediated tumor control was further supported by Atreya et al [46]. They showed that the expression of the T-box transcription factor eomesodermin, which is critically involved in controlling cytolytic activity of CD8+ T cells, inversely correlates to the occurrence of lymph node metastasis in CRC patients [46]. In contrast, Laghi et al [47] found that the density of CD3 + cells in the invasive margin of CRC could not be used as an independent predictor of survival, and at least for now, the TNM classification should remain the preferred prognostic system.…”

“…The data support the hypothesis that the adaptive immune response influences the behavior of human tumors. capacity determines the effectiveness of the immune system mediated tumor control was further supported by Atreya et al [46]. They showed that the expression of the T-box transcription factor eomesodermin, which is critically involved in controlling cytolytic activity of CD8+ T cells, inversely correlates to the occurrence of lymph node metastasis in CRC patients [46].…”

Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction

“…Previous reports indicated a role of Eomes in the control of effector proinflammatory Th subsets. Gain-and loss-of-function experiments in both CD8 + (14,21,38,59) and CD4 + (8,11,22,40) T cells have shown that Eomes promotes cytotoxicity and IFN-g production in mice and humans. However, none of these settings showed essential functions of Eomes for the induction of IFN-g, probably due to compensatory effects of the related transcription factor Tbet (21,22,57).…”

T-bet and Eomesodermin Are Required for T Cell-Mediated Antitumor Immune Responses

“…This suggests that the quality of T cells present within tumors is important for immune surveillance. Moreover, T-bet and Eomes were shown to be expressed in TILs of colorectal cancers, and the higher expression levels of these factors are correlated with better survival (7,20). T-bet-deficient mice are susceptible to prostate cancer metastasis (10).…”