Breast cancer prevention by prophylactic Lalba mRNA-LNP vaccination
(1) Nishida J (2) Seehawer M (3) Rojas Jimenez E (4) Yan P (5) Bui TM (6) Foidart P (7) Muramatsu H (8) Goyette MA (9) Cai X (10) Li Z (11) Beattie MB (12) Pardi N (13) Polyak K
Nishida et al. sought to prevent carcinogen (NMU)-induced mammary tumorigenesis in outbred Sprague-Dawley rats by targeting LALBA, a protein specifically expressed in luminal progenitor (LP) cells – the proposed cell-of-origin for breast cancer. Vaccination with N1-methylpseudouridine-modified Lalba mRNA-LNP induced antigen-specific immune responses, suppressed tumor incidence or progression, and extended tumor-free and overall survival. scRNAseq revealed a reduced frequency of proliferative LP cells upon vaccination, suggesting effective targeting of immunoreactive early mammary epithelial lesions.
Contributed by Ute Burkhardt
(1) Nishida J (2) Seehawer M (3) Rojas Jimenez E (4) Yan P (5) Bui TM (6) Foidart P (7) Muramatsu H (8) Goyette MA (9) Cai X (10) Li Z (11) Beattie MB (12) Pardi N (13) Polyak K
Nishida et al. sought to prevent carcinogen (NMU)-induced mammary tumorigenesis in outbred Sprague-Dawley rats by targeting LALBA, a protein specifically expressed in luminal progenitor (LP) cells – the proposed cell-of-origin for breast cancer. Vaccination with N1-methylpseudouridine-modified Lalba mRNA-LNP induced antigen-specific immune responses, suppressed tumor incidence or progression, and extended tumor-free and overall survival. scRNAseq revealed a reduced frequency of proliferative LP cells upon vaccination, suggesting effective targeting of immunoreactive early mammary epithelial lesions.
Contributed by Ute Burkhardt
ABSTRACT: 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.
Author Info:
(1) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. ROR: https://ror.org/02jzgtq86 Department of Medicine, Harvard Medical School, Boston, MA 02115.
Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. ROR: https://ror.org/04b6nzv94 (2) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. ROR: https://ror.org/02jzgtq86 Department of Medicine, Harvard Medical School, Boston, MA 02115. Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. ROR: https://ror.org/04b6nzv94 (3) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. ROR: https://ror.org/02jzgtq86 Department of Medicine, Harvard Medical School, Boston, MA 02115. Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. ROR: https://ror.org/04b6nzv94 (4) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. ROR: https://ror.org/02jzgtq86 Department of Medicine, Harvard Medical School, Boston, MA 02115. Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. ROR: https://ror.org/04b6nzv94 (5) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. ROR: https://ror.org/02jzgtq86 Department of Medicine, Harvard Medical School, Boston, MA 02115. Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. ROR: https://ror.org/04b6nzv94 (6) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. ROR: https://ror.org/02jzgtq86 Department of Medicine, Harvard Medical School, Boston, MA 02115. Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. ROR: https://ror.org/04b6nzv94 (7) Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (8) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. ROR: https://ror.org/02jzgtq86 Department of Medicine, Harvard Medical School, Boston, MA 02115. Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. ROR: https://ror.org/04b6nzv94 (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. ROR: https://ror.org/02jzgtq86 Department of Medicine, Harvard Medical School, Boston, MA 02115. Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. ROR: https://ror.org/04b6nzv94 (10) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. ROR: https://ror.org/02jzgtq86 Department of Medicine, Harvard Medical School, Boston, MA 02115. Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. ROR: https://ror.org/04b6nzv94 (11) Acuitas Therapeutics, Vancouver, BC, Canada V6T 1Z3. (12) Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104. ROR: https://ror.org/00b30xv10 (13) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215. ROR: https://ror.org/02jzgtq86 Department of Medicine, Harvard Medical School, Boston, MA 02115. Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. ROR: https://ror.org/04b6nzv94
Citation: Proc Natl Acad Sci U S A 2026 Sep 8 123:e2621855123 Epub09/02/2026
