Vaccine-Mediated Immunotherapy Directed against a Transcription Factor Driving the Metastatic Process

Abstract

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” due to 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 anti-tumor 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.

Epithelial–mesenchymal transition in colorectal cancer metastasis: A system review

“…To date, this is the first vaccine platform designed to target a driver of the EMT in tumors and has successfully reached the clinical stage [190]. Consistent with this, a recombinant yeast-TWIST1 vaccine also has anti-tumor effects that depend on TWIST1-specific CD8 + T-cells [191]. Together, these studies provide the rationale for vaccine-induced T-cell-mediated therapy with transcription factors involved in driving the metastatic process without toxic effects.…”

Immune Consequences of Decreasing Tumor Vasculature with Antiangiogenic Tyrosine Kinase Inhibitors in Combination with Therapeutic Vaccines

“…The total vascular area was similarly decreased in a second tumor model using 4T1 tumors in BALB/c mice treated with sunitinib and a vaccine targeting the transcription factor Twist (14, 16, 21, 22) (Suppl. Fig.…”

Immune evasion in cancer: Mechanistic basis and therapeutic strategies

“…It is fascinating how cancer cells migrate throughout the body from their original location to establish themselves at a new location [76]. How this exodus of tumor cells occurs is only now beginning to be understood.…”