Numerous reports have now demonstrated that the epithelial-to-mesenchymal transition (EMT) process is involved in solid
tumor progression,
metastasis, and drug resistance. Several
transcription factors have been implicated as drivers of EMT and metastatic progression, including Twist. Overexpression of Twist has been shown to be associated with poor prognosis and drug resistance for many
carcinomas and other
tumor types. The role of Twist in experimental
cancer metastases has been principally studied in the 4T1 mammary
tumor model, where silencing of Twist in vitro has been shown to greatly reduce in vivo metastatic spread.
Transcription factors such as Twist are generally believed to be "undruggable" because of their nuclear location and lack of a specific groove for tight binding of a small molecule inhibitor. An alternative approach to
drug therapy targeting
transcription factors driving the metastatic process is T-cell-mediated
immunotherapy. A therapeutic
vaccine platform that has been previously characterized consists of heat-killed recombinant Saccharomyces cerevisiae (yeast) capable of expressing
tumor-associated
antigen protein. We report here the construction and characterization of a recombinant yeast expressing the entire
Twist protein, which is capable of inducing both CD8(+) and CD4(+) Twist-specific T-cell responses in vivo. Vaccination of mice reduced the size of primary transplanted 4T1
tumors and had an even greater antitumor effect on lung
metastases of the same mice, which was dependent on Twist-specific CD8(+) T cells. These studies provide the rationale for
vaccine-induced T-cell-mediated
therapy of
transcription factors involved in driving the metastatic process.