Combination of CTLA-4 blockade with MUC1 mRNA nanovaccine induces enhanced anti-tumor CTL activity by modulating tumor microenvironment of triple negative breast cancer
| Autor: | Xuan Lin, Hedan Chen, Ying Xie, Xue Zhou, Yun Wang, Jing Zhou, Shiqi Long, Zuquan Hu, Shichao Zhang, Wei Qiu, Zhu Zeng, Lina Liu |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Translational Oncology Translational Oncology, Vol 15, Iss 1, Pp 101298-(2022) |
| ISSN: | 1936-5233 |
| Popis: | Highlights • Combined therapy with MUC1 mRNA nanovaccine and anti-CTLA-4 mAb could reduce immunosuppressive TME, increase the infiltration of CD8+ T cells into tumor sites, and enhance anti-tumor cytotoxic T-lymphocyte activity when compared with each monotherapy. • Combination treatment with anti-CTLA-4 mAb and MUC1 mRNA nanovaccine could appear more effective than either nanovaccine or anti-CTLA-4 mAb alone at increasing level of apoptosis in tumor cells. • Combination immunotherapy could significantly downregulated the signal transducer and activator of transcription 3 (STAT3) signal pathway. The immunosuppressive tumor microenvironment (TME) is the main reason for the failure of many immunotherapies that directly stimulate anti-tumor immune response. Anti-CTLA-4 antibody may reduce effector regulatory T (Treg) cell numbers and their suppressive activity in the TME. We have previously reported that combination of anti-CTLA-4 antibody with MUC1 mRNA nanovaccine may mutually enhance each single treatment. But the enhancement mechanism of therapeutic efficacy of MUC1 mRNA nanovaccine plus anti-CTLA-4 monoclonal antibody (mAb) is unknown. In this study, anti-tumor CTL activity induced by combination of CTLA-4 Blockade with MUC1 mRNA nanovaccine and immunosuppressive factors in the TME of triple negative breast cancer were investigated. The results demonstrated that combined therapy with nanovaccine and anti-CTLA-4 mAb could induce stronger anti-tumor CTL response than each monotherapy, result in significantly decreased numbers of myeloid-derived suppressor cells (MDSC), Treg cells, tumor-associated fibroblasts (TAFs) and tumor vasculature in the TME, downregulated levels of interleukin-6, tumor necrosis factor-α and transforming growth factor-β, and significantly upregulated levels of IFN-γ and interleukin-12 as well as increased number of CD8+ T cell, and appear more effective than either nanovaccine or anti-CTLA-4 mAb alone at increasing level of apoptosis in tumor cells. In addition, combination immunotherapy could significantly downregulated the signal transducer and activator of transcription 3 (STAT3) signal pathway. Therefore, it can be concluded that combination of CTLA-4 blockade with MUC1 mRNA nanovaccine enhances anti-tumor cytotoxic T-lymphocyte activity by reducing immunosuppressive TME and inhibiting tumor-promoting STAT3 signaling pathway. |
| Databáze: | OpenAIRE |
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