Encouraged by predicted structural differences between HER2 and its oncogenic splice variant (Δ16HER2), Bartolacci and Andreani et al. developed DNA vaccines against both isoforms. Both vaccines induced a specific antibody response and protected mice from transplantable, Δ16HER2-expressing breast cancers, but failed to elicit a response in Δ16HER2 transgenic mice that develop spontaneous tumors. Bacteriophages expressing the entire Δ16HER2 extracellular domain or specific epitopes from the novel splice junction broke immune tolerance, delayed tumor growth, and reduced the number and size of tumors in transgenic mice.
Delta16HER2 is a splice variant of HER2 and defined as the transforming isoform in HER2-positive breast cancer. It has been shown that Delta16HER2 promotes breast cancer aggressiveness and drug resistance. In the present work, we used in silico modelling to identify structural differences between Delta16HER2 and the wild-type HER2 proteins. We then developed DNA vaccines specifically against the Delta16HER2 isoform and showed that these immunotherapies hampered carcinogenesis in a breast cancer transplantable model. However, the vaccines failed to elicit immune protection in Delta16HER2 transgenic mice because of tolerogenic mechanisms towards the human HER2 self-antigen, a scenario commonly seen in HER2+ patients. Thus, we engineered bacteriophages with immunogenic epitopes of Delta16HER2 exposed on their coat for use as anticancer vaccines. These phage-based vaccines were able to break immune tolerance, triggering a protective anti-Delta16HER2 humoral response. These findings provide a rationale for the use of phage-based anti-HER2/Delta16HER2 vaccination as a safe and efficacious immunotherapy against HER2-positive breast cancers.
Author Info: (1) Department of Biosciences and Veterinary Medicine, University of Camerino. (2) Department of Biosciences and Veterinary Medicine, University of Camerino. (3) Aging Research Cen
Author Info: (1) Department of Biosciences and Veterinary Medicine, University of Camerino. (2) Department of Biosciences and Veterinary Medicine, University of Camerino. (3) Aging Research Centre, G. d'Annunzio University. (4) Biotecnologie Molecolari e Scienze per la Salute, University of Torino. (5) Dipartimento di Scienze della Vita e dell'Ambiente, Universita Politecnica delle Marche. (6) Biotecnologie Molecolari e Scienze per la Salute, University of Torino. (7) Dipartimento di Scienze della Vita e dell'Ambiente, Universita Politecnica delle Marche. (8) Department of Medicine and Aging Science, Center of Excellence on Aging and Translational Medicine (CeSi-Met), CeSI-Met, 'G. D'Annunzio' University of Chieti-Pescara. (9) Department of Biosciences and Veterinary Medicine, University of Camerino. (10) Department of Biosciences and Veterinary Medicine, University of Camerino. (11) Department of Biosciences and Veterinary Medicine, University of Camerino. (12) Department of Biosciences and Veterinary Medicine, University of Camerino. (13) Department of Biosciences and Veterinary Medicine, University of Camerino augusto.amici@unicam.it.
