Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells.
Epithelial-mesenchymal transition (EMT) is a key step toward cancer metastasis, and Snail is a major transcription factor governing EMT. Here, we demonstrate that Snail-induced EMT accelerates cancer metastasis through not only enhanced invasion but also induction of immunosuppression. Murine and human melanoma cells with typical EMT features after snail transduction induced regulatory T cells and impaired dendritic cells in vitro and in vivo partly through TSP1 production. Although Snail(+) melanoma did not respond to immunotherapy, intratumoral injection with snail-specific siRNA or anti-TSP1 monoclonal antibody significantly inhibited tumor growth and metastasis following increase of tumor-specific tumor-infiltrating lymphocytes and systemic immune responses. These results suggest that inhibition of Snail-induced EMT could simultaneously suppress both tumor metastasis and immunosuppression in cancer patients.
Kudo-Saito
Chie
C
Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan. kudoc@sc.itc.keio.ac.jp
Shirako
Hiromi
H
Takeuchi
Tadashi
T
Kawakami
Yutaka
Y
D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance; D007150:Immunohistochemistry; D007167:Immunotherapy; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology*; D009361:Neoplasm Invasiveness / Q000276:immunology*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic; D014162:Transfection
D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors