Abstract
Abstract Triple negative breast cancer (TNBC) is characterized by higher relapse and poor survival rates compared to other breast cancer types and is marked by a cancer stem cell (CSC)/epithelial to mesenchymal transition (EMT) signature. We questioned whether a vaccine targeting CSC/EMT associated proteins could prevent development of TNBC. We identified five overexpressed proteins found in TNBC and associated with different CSC/EMT pathways. We used a scoring system derived from three common algorithms for predicting class II MHC binding to select Th epitopes for CD105, CDH3, MDM2, SOX-2 and YB-1. Those epitopes that induced a selective Th1 (IFN-gamma) immune response in human population based screening were included in a multi-antigen vaccine. Epitopes were highly homologous between mouse and man. Immunization with the multi-antigen vaccine induced Th1 specific for all five antigens compared to adjuvant control (p<0.05 for all). Immunity persisted 3 months after the final vaccine (p<0.05 for all). Vaccination generated an antigen-specific cytotoxic T-cell (CTL) immune response to three antigens (p<0.05). The vaccine increased effector memory T-cells by 2-fold compared to control (p=0.03). Tumor growth in vaccinated FVB-Tg(C3-1-TAg) mice, a basal breast cancer model, was inhibited by over 80% compared to control mice (p<0.0001). We observed significantly more CTL (p=0.04) and Th1 (p<0.001) infiltrating the tumor with a concomitant reduction in cells expressing the stem cell marker Sca-1 (p=0.003) after immunization with vaccine compared to control. This multi-antigen vaccine targeting CSC/EMT antigens is currently being investigated in a Phase I clinical trial (NCT02157051).
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