Journal
MOLECULAR THERAPY
Volume 26, Issue 1, Pages 45-55Publisher
CELL PRESS
DOI: 10.1016/j.ymthe.2017.10.020
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Funding
- NIH [CA149363, CA151652, CA149387]
- Science and Technology Foundation of Guizhou Province [LH-2015-7318, J-2016-1118]
- State Scholarship Fund of China Scholarship Council(CSC) [201308525104]
- NATIONAL CANCER INSTITUTE [U54CA198999, R01CA149387, U54CA151652, P30CA016086, R01CA149363] Funding Source: NIH RePORTER
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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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