A Synthetic CD8α:MyD88 Coreceptor Enhances CD8+ T-cell Responses to Weakly Immunogenic and Lowly Expressed Tumor Antigens
| Autor: | Yuji Zhang, Sabina Kaczanowska, Cruz Velasco Gonzales, Jackline Joy Martín Lasola, Eduardo Davila, Kenisha Younger, Ann Mary Joseph, Jitao Guo, Alexander K Tsai |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research CD30 Chemistry T cell T-cell receptor CD28 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Immunology Cancer research medicine Cytotoxic T cell IL-2 receptor Antigen-presenting cell CD8 |
| Zdroj: | Cancer Research. 77:7049-7058 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-17-0653 |
| 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 costimulatory molecules in a tumor antigen–dependent manner. These effects were accompanied by elevated activation of TCR and Toll-like receptor signaling-related proteins. CD8α:MyD88–expressing T cells improved antitumor responses in mice. Enhanced antitumor 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. Cancer Res; 77(24); 7049–58. ©2017 AACR. |
| Databáze: | OpenAIRE |
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