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Investigation of the mechanisms of tissue factor-mediated evasion of tumour cells from cellular cytotoxicity

Li, Chao; Collier, Mary E. W.; Collier, Mary; Frentzou, G. Alkisitis; Greenman, John; Collier, Mary E W; Frentzou, A; Ettelaie, Camille

Authors

Chao Li

Mary E. W. Collier

Mary Collier M.Collier@hull.ac.uk

G. Alkisitis Frentzou

Mary E W Collier

A Frentzou

Camille Ettelaie C.Ettelaie@hull.ac.uk



Abstract

Aims We previously reported that overexpression of tissue factor (TF) protected HT29 tumour cells from cellular cytotoxicity through a mechanism requiring the presence of the cytoplasmic domain of TF. In this investigation the mechanism of TF-mediated immune evasion has been examined. Methods The influence of alanine-substitution at Ser253 and Ser258 of TF (TFAla253 and TF (Ala258)) on the induction of cytotoxic evasion, as well as expression of vascular cell adhesion molecule-1 and intra-cellular adhesion molecule-1 (VCAM-1 and ICAM-1) was investigated. Moreover, we examined the effect of transfection of four 20-mer peptides, corresponding to the C-terminal residues of TF, with different phosphorylation states, on promotion of evasion from cell cytotoxicity. Results Cells overexpressing TFAla258 and to a lesser extent overexpressing TFAla253, exhibited a reduced ability to evade cellular cytotoxicity compared to cells overexpressing the wild-type TF. Furthermore, the increase in protection acquired was greatest on transfection of Ser258-phosphsorylated form of the cytoplasmic peptide, lower in double-phosphorylated and Ser253-phosphorylated peptides respectively, and lowest in the unphosphorylated form. Finally, the expression of VCAM-1 mRNA as well as surface antigen was reduced on overexpression of TFwt but was partially reverted in the cells transfected to overexpress TFAla253 or TFAla258. Conclusions These data show that the phosphorylation of TF at Ser258 and to a lesser extent Ser253, plays an essential role in the protective influence of TF on immune evasion by tumour cells, and that the mechanism could involve the downregulation of key surface antigens, such as adhesion proteins, involved in cell:cell interaction.

Journal Article Type Article
Publication Date 2008-09
Journal CANCER IMMUNOLOGY IMMUNOTHERAPY
Print ISSN 0340-7004
Electronic ISSN 1432-0851
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 57
Issue 9
Pages 1347-1355
APA6 Citation Li, C., Collier, M. E. W., Frentzou, G. A., Greenman, J., & Ettelaie, C. (2008). Investigation of the mechanisms of tissue factor-mediated evasion of tumour cells from cellular cytotoxicity. Cancer Immunology, Immunotherapy, 57(9), 1347-1355. doi:10.1007/s00262-008-0469-6
DOI https://doi.org/10.1007/s00262-008-0469-6
Keywords Tissue factor cancer tumour immune-evasion cytotoxicity
Publisher URL http://www.springerlink.com/content/423525284161vm43/
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