Breast cancer prevention by prophylactic Lalba mRNA-LNP vaccination
Menée sur des rats, cette étude démontre qu'un vaccin à nanoparticules lipidiques chargées en ARN messager codant pour l'alpha-lactalbumine bloque la tumorigenèse mammaire et améliore la survie sans présenter de toxicité pour les cellules saines
Early-stage tumors are the most favorable setting for cancer interception because tumor-suppressive immunity is stronger before cancers become advanced. Here, a prophylactic lipid nanoparticle–encapsulated mRNA vaccine targeting alpha-lactalbumin (LALBA), a protein unique to mammary luminal progenitors (LPs), was developed to test whether strengthening immune response against a putative breast cancer cell-of-origin can suppress tumorigenesis. In outbred Sprague-Dawley rats, vaccination with Lalba mRNA-LNP lowered the incidence of carcinogen-induced mammary tumors and improved both tumor-free and overall survival, without obvious toxicity in normal mammary tissue or other organs. Single-cell transcriptomic analysis further showed that vaccination decreased a proliferative LP population in immunoreactive early epithelial hyperplasia, supporting the potential of prophylactic Lalba mRNA-LNP to block the initiation and progression of early breast neoplastic lesions. Tumor-suppressive immunity is more evident in early-stage compared to advanced tumors making it the ideal point for cancer interceptive immunotherapies. We previously described that higher peripheral T cell diversity is associated with more pronounced CD8+ T cell infiltration in ductal carcinoma in situ of the breast, implying a close interaction between peripheral and intratumor immunity. Here, we developed lipid nanoparticle (LNP)-encapsulated messenger ribonucleic acid (mRNA) vaccines expressing the alpha-lactalbumin (LALBA) protein unique to mammary luminal progenitors (LPs) to test whether enhancing immune response by prophylactic vaccination against the putative cell-of-origin of breast cancer suppresses tumorigenesis. Vaccination of outbred Sprague-Dawley rats with N1-methylpseudouridine-modified or unmodified Lalba mRNA-LNP induced different degrees of LALBA-specific and nonspecific immune responses. The vaccination suppressed carcinogen-induced mammary tumorigenesis and improved tumor-free and overall survival without obvious toxicity in the normal mammary glands and other organs. Single-cell transcriptomic analysis revealed that vaccination decreases the frequency of a proliferative LP population in immunoreactive early epithelial hyperplasia. Overall, we provide proof of principle that prophylactic Lalba mRNA-LNP has the potential to suppress the initiation and progression of early breast neoplastic lesions.
Proceedings of the National Academy of Sciences , article en libre accès, 2026