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.

[1]  J. Talmadge Pathways Mediating the Expansion and Immunosuppressive Activity of Myeloid-Derived Suppressor Cells and Their Relevance to Cancer Therapy , 2007, Clinical Cancer Research.

[2]  C. Berking,et al.  Lessons from melanocyte development for understanding the biological events in naevus and melanoma formation , 2000, Melanoma research.

[3]  A. Aigner,et al.  RNAi-mediated gene-targeting through systemic application of polyethylenimine (PEI)-complexed siRNA in vivo , 2005, Gene Therapy.

[4]  L. Ellis,et al.  Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells. , 2006, Cancer research.

[5]  A. Bosserhoff,et al.  Snail-regulated genes in malignant melanoma , 2005, Melanoma research.

[6]  H. Aburatani,et al.  Role of Thrombospondin-1 in T Cell Response to Ocular Pigment Epithelial Cells12 , 2007, The Journal of Immunology.

[7]  G. Gallick,et al.  Development and Characterization of Gemcitabine-Resistant Pancreatic Tumor Cells , 2007, Annals of Surgical Oncology.

[8]  S. Chiou,et al.  Overexpression of NBS1 induces epithelial–mesenchymal transition and co-expression of NBS1 and Snail predicts metastasis of head and neck cancer , 2007, Oncogene.

[9]  C. N. Coleman,et al.  The Requirement of Multimodal Therapy (Vaccine, Local Tumor Radiation, and Reduction of Suppressor Cells) to Eliminate Established Tumors , 2005, Clinical Cancer Research.

[10]  Y. Kawamoto,et al.  Essential Roles of CD8+CD122+ Regulatory T Cells in the Maintenance of T Cell Homeostasis , 2004, The Journal of experimental medicine.

[11]  H. von Boehmer,et al.  Mechanisms of suppression by suppressor T cells , 2005, Nature immunology.

[12]  B. Rouse Regulatory T cells in health and disease , 2007, Journal of internal medicine.

[13]  T. Waldmann Effective cancer therapy through immunomodulation. , 2006, Annual review of medicine.

[14]  H. Beug,et al.  Molecular requirements for epithelial-mesenchymal transition during tumor progression. , 2005, Current opinion in cell biology.

[15]  H. Höfler,et al.  Analysis of the E-Cadherin Repressor Snail in Primary Human Cancers , 2007, Cells Tissues Organs.

[16]  D. Radisky Epithelial-mesenchymal transition , 2005, Journal of Cell Science.

[17]  Y. Li,et al.  Clinical, immunological, and pathological aspects of operational tolerance after pediatric living-donor liver transplantation. , 2007, Transplant immunology.

[18]  K. Sugimachi,et al.  Transcriptional repressor snail and progression of human hepatocellular carcinoma. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[19]  M. Bittner,et al.  The Wnt5A/Protein Kinase C Pathway Mediates Motility in Melanoma Cells via the Inhibition of Metastasis Suppressors and Initiation of an Epithelial to Mesenchymal Transition* , 2007, Journal of Biological Chemistry.

[20]  J. Abe,et al.  Thrombospondin 1 Is an Autocrine Negative Regulator of Human Dendritic Cell Activation , 2003, The Journal of experimental medicine.

[21]  A. Sica,et al.  Tumor promotion by tumor-associated macrophages. , 2007, Advances in experimental medicine and biology.

[22]  S. Rosenberg,et al.  Cancer immunotherapy: moving beyond current vaccines , 2004, Nature Medicine.

[23]  J. Clements,et al.  Epithelial—mesenchymal and mesenchymal—epithelial transitions in carcinoma progression , 2007, Journal of cellular physiology.

[24]  Robert D Cardiff,et al.  The transcriptional repressor Snail promotes mammary tumor recurrence. , 2005, Cancer cell.

[25]  E. Hay An overview of epithelio-mesenchymal transformation. , 1995, Acta anatomica.

[26]  H. Kajiyama,et al.  Chemoresistance to paclitaxel induces epithelial-mesenchymal transition and enhances metastatic potential for epithelial ovarian carcinoma cells. , 2007, International journal of oncology.

[27]  M. Beyer,et al.  Regulatory T cells in cancer. , 2006, Blood.

[28]  M. Quintanilla,et al.  TGF β induces Snail transcription factor Transforming growth factor beta 1 induces Snail transcription factor in epithelial cell lines , 2003 .

[29]  R. Hynes,et al.  Thrombospondin-1 is a major activator of TGF-beta1 in vivo. , 1998, Cell.

[30]  B. Bisikirska,et al.  TCR stimulation with modified anti-CD3 mAb expands CD8+ T cell population and induces CD8+CD25+ Tregs. , 2005, The Journal of clinical investigation.

[31]  A. Rudensky,et al.  Regulation of immunity by self-reactive T cells , 2005, Nature.