Chie Kudo-Saito and colleagues transduced B16-F10 murine melanoma cells with SNAI1, which led to an EMT-like phenotype. They found that the expression of the transcription factor forkhead box protein P3 (FOXP3, an important mediator of the immunosuppressive function of regulatory T cells) was induced in the CD4+ T-regulatory (TReg) cells present in a population of spleen cells (SPCs) co-cultured with SNAI1+ tumour cells. The CD4+FOXP3+TReg cells suppressed T cell proliferation in the co-culture.
How are TReg cells activated by cells that have undergone EMT? The authors examined the cytokines transforming growth factor-β (TGFβ), interleukin 10 (IL-10) and thrombospondin 1 (TSP1), which have been previously implicated in TReg cell induction, and found that the levels of TGFβ and TSP1 were significantly increased in SNAI1+ melanoma cells. Treatment of SPC and SNAI1+ tumour cell co-cultures with an anti-TSP1 monoclonal antibody reduced the induction of CD4+FOXP3+ TRegcells. Furthermore, natural induction of EMT by treatment with TGFβ or tumour necrosis factor-α (TNFα) also increased SNAI1 levels in B16-F10 cells and led to immunosuppression. The authors observed a similar relationship between naturally or SNAI1-induced EMT and immunosuppression in several human melanoma cell lines. They also observed the phenomenon in retinal pigment epithelial cells, suggesting that SNAI1-induced EMT might cause immunosuppression even in non-cancerous cells.
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