A Synthetic CD8α:MyD88 Coreceptor Enhances CD8
| Autor: | Sabina, Kaczanowska, Ann Mary, Joseph, Jitao, Guo, Alexander K, Tsai, Jackline Joy, Lasola, Kenisha, Younger, Yuji, Zhang, Cruz Velasco, Gonzales, Eduardo, Davila |
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| Rok vydání: | 2017 |
| Předmět: |
Cytotoxicity
Immunologic Antigen Presentation CD8 Antigens Recombinant Fusion Proteins Mice Transgenic Dendritic Cells CD8-Positive T-Lymphocytes Article Gene Expression Regulation Neoplastic Mice Inbred C57BL Mice Antigens Neoplasm Neoplasms Myeloid Differentiation Factor 88 Immune Tolerance Animals Humans Cells Cultured |
| Zdroj: | Cancer research. 77(24) |
| ISSN: | 1538-7445 |
| Popis: | T cell-based immunotherapies are a promising approach for patients with advanced cancers. However, various obstacles limit T cell efficacy, including suboptimal T cell receptor (TCR) activation and an immunosuppressive tumor environment. Here we developed a fusion protein by linking CD8α and MyD88 (CD8α:MyD88) to enhance CD8+ T cell responses to weakly immunogenic and poorly expressed tumor antigens. CD8α:MyD88-engineered T cells exhibited increased proliferation and expression of effector and co-stimulatory molecules in a tumor antigen-dependent manner. These effects were accompanied by elevated activation of TCR and Toll-like receptor (TLR) signaling-related proteins. CD8α:MyD88-expressing T cells improved anti-tumor responses in mice. Enhanced anti-tumor activity was associated with a unique tumor cytokine/chemokine signature, improved T cell infiltration, reduced markers of T cell exhaustion, elevated levels of proteins associated with antigen presentation, and fewer macrophages with an immunosuppressive phenotype in tumors. Given these observations, CD8α:MyD88 represents a unique and versatile approach to help overcome immunosuppression and enhance T cell responses to tumor antigens. |
| Databáze: | OpenAIRE |
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