Combination Immunotherapy of MUC1 mRNA Nano-vaccine and CTLA-4 Blockade Effectively Inhibits Growth of Triple Negative Breast Cancer
Open accessAbstract
Triple negative breast cancer (TNBC), which constitutes 10%-20% of all breast cancers, is associated with aggressive progression, a high rate of metastasis, and poor prognosis. The treatment of patients with TNBC remains a great clinical challenge. Preclinical reports support the combination immunotherapy of cancer vaccines and immune checkpoint blockades in non-immunogenic tumors. In this study, we constructed nanoparticles (NPs) to deliver an mRNA vaccine encoding tumor antigen MUC1 to dendritic cells (DCs) in lymph nodes to activate and expand tumor-specific T cells. An anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) monoclonal antibody was combined with the mRNA vaccine to enhance the anti-tumor benefits. In vivo studies demonstrated that the NP-based mRNA vaccine, targeted to mannose receptors on DCs, could successfully express tumor antigen in the DCs of the lymph node; that the NP vaccine could induce a strong, antigen-specific, in vivo cytotoxic T lymphocyte response against TNBC 4T1 cells; and that combination immunotherapy of the vaccine and anti-CTLA-4 monoclonal antibody could significantly enhance anti-tumor immune response compared to the vaccine or monoclonal antibody alone. These data support both the NP as a carrier for delivery of mRNA vaccine and a potential combination immunotherapy of the NP-based mRNA vaccine and the CTLA-4 inhibitor for TNBC.
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Mannose-modified lipid nanoparticle-mRNA formulations are preferentially taken up by dendritic cells.
“To further improve vaccine efficacy, APC uptake and T cell activation can be optimized; for example, mannose-modified lipid nanoparticle–mRNA formulations are preferentially taken up by dendritic cells150,201,202.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [201]
Accumulating pre-clinical evidence shows that T cell responses and antitumor effects evoked by mRNA cancer therapeutics can strongly be strengthened by combining them with checkpoint inhibitors, such as anti-PD-1(L)- and anti-CTLA-4 antibodies.
“Indeed, accumulating pre-clinical evidence shows that T cell responses and antitumor effects evoked by mRNA cancer therapeutics can strongly be strengthened by combining them with checkpoint inhibitors, such as anti-PD-1(L)-, and also anti-CTLA-4 antibodies [135,196,214,218,219].”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [219]
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References 53 · Cited by 373
- Authors
- Liu, L., Wang, Y., Miao, L., Liu, Q., Musetti, S., Li, J., & Huang, L.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Huang, Leaf
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 26
- Issue
- 1
- Pages
- 45-55
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC5763160
- OpenAlex
- W2774223113
- Cited by
- 373
- References
- 53
- Citations by year
- 2026: 29 · 2025: 41 · 2024: 63 · 2023: 48 · 2022: 64 · 2021: 51 · 2020: 33 · 2019: 23 · 2018: 21
- FWCI
- 9.53
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- NIH (CA149363, CA151652, CA149387)
- State Scholarship Fund of China Scholarship Council (201308525104)
- Science and Technology Foundation of Guizhou Province (LH-2015-7318, J-2016-1118)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- triple-negative breast cancer, MUC1, mRNA vaccines, nanoparticle vaccine delivery, CTLA-4 blockade, combination immunotherapy, dendritic cells, mannose receptor targeting, tumor-specific T cells, 4T1 cells, antitumor immunity, cancer vaccines
- MeSH terms
- Animals, Antigens, Neoplasm, Combined Modality Therapy, Dendritic Cells, Disease Models, Animal, Female, Humans, Immunotherapy, Interferon-gamma, Lymph Nodes, Recombinant Fusion Proteins, T-Lymphocytes, Cytotoxic, Lymphocytes, Tumor-Infiltrating, Mucin-1, Antineoplastic Agents, Hormonal, Cancer Vaccines, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, CTLA-4 Antigen, Triple Negative Breast Neoplasms
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