Phage-based anti-HER2 vaccination can circumvent immune tolerance against breast cancer

D16HER2 is a splice variant of HER2 and defined as the transforming isoform in HER2-positive breast cancer. It has been shown that D16HER2 promotes breast cancer aggressiveness and drug resistance. In the present work, we used in silico modeling to identify structural differences between D16HER2 and the wild-type HER2 proteins. We then developed DNA vaccines specifically against the D16HER2 isoform and showed that these immunotherapies hampered carcinogenesis in a breast cancer transplantable model. However, the vaccines failed to elicit immune protection in D16HER2 transgenic mice because of tolerogenic mechanisms toward the human HER2 self-antigen, a scenario commonly seen in HER2þ patients. Thus, we engineered bacteriophages with immunogenic epitopes of D16HER2 exposed on their coat for use as anticancer vaccines. These phage-based vaccines were able to break immune tolerance, triggering a protective anti-D16HER2 humoral response. These findings provide a rationale for the use of phage-based anti-HER2/D16HER2 vaccination as a safe and efficacious immunotherapy against HER2-positive breast cancers.