Immunosuppressive mechanisms induced by tumor cells during epithelial-mesenchymal transition leading to tumor metastasis

2465 Purpose: Epitherial-mesenchymal transition (EMT) is a dynamic trans-differentiation process to acquire cell mobility for body organization such as embryonic development or wound healing, and characterized by decreased epitherial features and increased mesenchymal features. EMT is recently reported to be a key step toward tumor metastasis, which is still a critical issue in cancer therapy. Many EMT inducers are identified, and the molecular mechanisms in tumor cells have been elucidated in detail. However, the interaction between host immunity and tumor cells during EMT has not investigated yet. We hypothesized that during EMT, tumor cells might negatively influence host immune system to escape efficiently. In this study, we established human pancreatic cancer cell line Panc-1 cells transduced with snail gene, which is an essential transcription factor governing EMT, and then analyzed effect of the snail transfectant on immune responses.
 Results: When human PBMCs were co-cultured with the snail transfectants showing typical EMT features (increased migration/invasion with less E-cadherin expression), CD11c+ cell differentiation was significantly inhibited, and CD4+CD25-cells were transformed into immunosuppressive cells with increased FoxP3 expression, as compared with those to the parental cells or mock-transfected cells. The role of snail expression in tumor cells for the immunosuppression were determined by snail knockdown using snail-specific siRNA. Such induction of immunosuppressive cells was also observed in vivo where SCID mice were injected with human PBMCs and the snail transfectant. We conducted GeneChip array analysis to compare gene expression between snail transfectants and the parental cells, particularly focusing on immunoregulatory molecules, and identified the specific mediators involved in the effects induced by snail transfectants.
 Conclusion: We demonstrate that snail expression in tumor cells induces the immunosuppressive microenvironment involving impaired dendritic cells and regulatory T cells, resulting in promotion of tumor metastasis. Blockade of the molecules identified is effective in simultaneously suppressing both tumor metastasis and immunosuppression. This strategy targeting such factors commonly regulating both tumor metastasis and immunosuppression could possibly improve anti-tumor efficacies induced by a range of therapies for cancer patients.