Engineering Active IKKβ in T Cells Drives Tumor Rejection1
| Autor: | Evaristo, César, Spranger, Stefani, Barnes, Sarah E., Miller, Michelle L., Molinero, Luciana L., Locke, Frederick, Gajewski, Thomas F., Alegre, Maria-Luisa |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Cytotoxicity
Immunologic T-Lymphocytes NF-kappa B Gene Expression Mice Transgenic CD8-Positive T-Lymphocytes Adoptive Transfer Article I-kappa B Kinase Tumor Burden Disease Models Animal Interferon-gamma Mice Lymphocytes Tumor-Infiltrating Cell Line Tumor Neoplasms Animals Heterografts Humans Lymphocyte Count Genetic Engineering Signal Transduction |
| Popis: | Acquired dysfunction of tumor-reactive T cells is one mechanism by which tumors can evade the immune system. Identifying and correcting pathways that contribute to such dysfunction should enable novel anticancer therapy design. During cancer growth, T cells show reduced NF-κB activity, which is required for tumor rejection. Impaired T cell-intrinsic NF-κB may create a vicious cycle conducive to tumor progression and further T cell dysfunction. We hypothesized that forcing T cell-intrinsic NF-κB activation might break this cycle and induce tumor elimination. NF-κB was activated in T cells by inducing the expression of a constitutively active form of the upstream activator IκB kinase β (IKKβ). T cell-restricted constitutively active IKKβ augmented the frequency of functional tumor-specific CD8(+) T cells and improved tumor control. Transfer of constitutively active IKKβ-transduced T cells also boosted endogenous T cell responses that controlled pre-established tumors. Our results demonstrate that driving T cell-intrinsic NF-κB can result in tumor control, thus identifying a pathway with potential clinical applicability. |
| Databáze: | OpenAIRE |
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