TGF-β1 promotes colorectal cancer immune escape by elevating B7-H3 and B7-H4 via the miR-155/miR-143 axis.

Transforming growth factor-beta 1 (TGF-β1) suppresses T cell function， promoting tumor immune escape. Yet， whether the depression of TGF-β1 on T cell function is mediated by co-inhibitory molecules B7-H3 and B7-H4 remains largely unclear. Here， we demonstrated that TGF-β1 elevated the expression of miR-155 in colorectal cancer cells through SMAD3 and SMAD4. The upregulated miR-155 attenuated miR-143 by inhibiting its direct target， the transcription factor CEBPB. Consequently， the direct target genes of miR-143， B7-H3 and B7-H4， were augmented in the cytoplasm and membrane of tumor cells. Over-expression of B7-H3 and B7-H4 in HCT-116 cells induced T cells to secrete TGF-β1 and the immunosuppressive cytokines IL-2， IL-6， and IL-17. Restoration of miR-143 inhibited the growth of HCT-116 xenograft tumors in mice， and also repressed the expression of B7-H3 and B7-H4 in the tumors. Thus， this study reveals the mechanism by which TGF-β1 leads to T cell-mediated tumor evasion through an increase in B7-H3 and B7-H4 expression.