Combination Immunotherapy of MUC1 mRNA Nano-vaccine and CTLA-4 Blockade Effectively Inhibits Growth of Triple Negative Breast Cancer

TLDR

Triple‑negative breast cancer is an aggressive subtype with high metastasis and poor prognosis, and current treatments remain inadequate; preclinical studies suggest that combining cancer vaccines with immune‑checkpoint blockade can be effective in non‑immunogenic tumors. The authors constructed nanoparticles to deliver an MUC1‑encoding mRNA vaccine to dendritic cells in lymph nodes, aiming to activate and expand tumor‑specific T cells. The vaccine nanoparticles targeted mannose receptors on dendritic cells and were combined with an anti‑CTLA‑4 monoclonal antibody to amplify anti‑tumor immunity. In vivo, the NP‑based vaccine induced strong antigen‑specific cytotoxic T‑cell responses against TNBC 4T1 cells, and the addition of anti‑CTLA‑4 markedly enhanced the anti‑tumor effect compared to either agent alone, supporting the NP as a delivery platform and the combination strategy for TNBC.

Abstract

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.