T11TS immunotherapy repairs PI3K‐AKT signaling in T‐cells: Clues toward enhanced T‐cell survival in rat glioma model
| Autor: | Manoj Kumar Singh, Omar Faruk Sk, Larance Ronsard, Iman Hazra, Suhnrita Chaudhuri, Swapna Chaudhuri, Somnath Mondal, Debanjan Bhattacharya, Ankur Datta, Tushar Kanti Ghosh |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Cell Survival Physiology T-Lymphocytes medicine.medical_treatment T cell Clinical Biochemistry Active Transport Cell Nucleus Antineoplastic Agents Biology Immunological synapse 3-Phosphoinositide-Dependent Protein Kinases 03 medical and health sciences 0302 clinical medicine CD28 Antigens Glioma medicine Animals PTEN Phosphorylation Protein kinase B PI3K/AKT/mTOR pathway Brain Neoplasms NF-kappa B PTEN Phosphohydrolase Cell Biology Immunotherapy CD58 Antigens medicine.disease Rats 030104 developmental biology medicine.anatomical_structure Apoptosis Ethylnitrosourea 030220 oncology & carcinogenesis Immunology Cancer research biology.protein Female Tumor Escape Phosphatidylinositol 3-Kinase Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Journal of Cellular Physiology. 233:759-770 |
| ISSN: | 1097-4652 0021-9541 |
| DOI: | 10.1002/jcp.26047 |
| Popis: | Malignant glioma is the most fatal of astrocytic lineage tumors despite therapeutic advances. Onset and progression of gliomas is accompanied by severe debilitation of T-cell defense and T-cell survival. One of the chief contributors to T-cell survival downstream of activation is the PI3K-AKT pathway. Our prior studies showed that the novel immunotherapeutic molecule T11-target structure (T11TS) blocks T-cell apoptosis in glioma. We also showed activation of immunological synapse components and calcineurin-NFAT pathway following T11TS immunotherapy of glioma-bearing rats. This lead to investigations whether such T-cell activation upon T11TS therapy translates into activation of downstream PI3K/AKT signals which may be related to observed blockade of T-cell apoptosis. For the purpose, we assessed by flowcytometry and immunoblotting, expressions of PI3K, PDK1, AKT, p-AKT, and PTEN in splenic T-cells of normal, experimentally-induced glioma-bearing rats and glioma-bearing rats receiving first, second and third doses of T11TS. We also determined comparative nuclear translocation of NF-κB across groups. We found significant increases in T-cell expressions of PDK1, PI3K, and p-AKT in T11TS-treated animal groups compared to sharp downregulations in glioma. AKT levels remained unchanged across groups. PTEN levels declined sharply after T11TS immunotherapy. T11TS also caused enhanced NF-κB translocation to the T-cell nucleus compared to glioma group. Results showed heightened activation of the PI3K-AKT pathway in glioma-bearing rats following T11TS immunotherapy. These results illustrate the novel role of T11TS immunotherapy in ameliorating the PI3K pathway in T-cells in glioma-bearing animals to enhance T-cell survival, according greater defense against glioma. The study thus has far-reaching clinical outcomes. |
| Databáze: | OpenAIRE |
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