Inhibition of STAT3 Promotes the Efficacy of Adoptive Transfer Therapy Using Type-1 CTLs by Modulation of the Immunological Microenvironment in a Murine Intracranial Glioma
| العنوان: | Inhibition of STAT3 Promotes the Efficacy of Adoptive Transfer Therapy Using Type-1 CTLs by Modulation of the Immunological Microenvironment in a Murine Intracranial Glioma |
|---|---|
| المؤلفون: | Mitsugu Fujita, Ian F. Pollack, Hideho Okada, Keri L. Low, Ryo Ueda, Xinmei Zhu, Kotaro Sasaki |
| المصدر: | The Journal of Immunology. 180:2089-2098 |
| بيانات النشر: | The American Association of Immunologists, 2008. |
| سنة النشر: | 2008 |
| مصطلحات موضوعية: | STAT3 Transcription Factor, Chemokine, Adoptive cell transfer, T cell, Immunology, Mice, Nude, CD11c, Mice, Transgenic, Mice, T-Lymphocyte Subsets, Cell Line, Tumor, Glioma, medicine, Animals, Immunology and Allergy, Cytotoxic T cell, Phosphorylation, Cells, Cultured, Injections, Intraventricular, biology, Brain Neoplasms, business.industry, Cell Migration Inhibition, medicine.disease, Acquired immune system, Adoptive Transfer, Combined Modality Therapy, Triterpenes, Mice, Inbred C57BL, medicine.anatomical_structure, biology.protein, business, Neoplasm Transplantation, T-Lymphocytes, Cytotoxic |
| الوصف: | A variety of cancers, including malignant gliomas, show aberrant activation of STAT3, which plays a pivotal role in negative regulation of antitumor immunity. We hypothesized that inhibition of STAT3 signals would improve the efficacy of T cell adoptive transfer therapy by reversal of STAT3-induced immunosuppression in a murine GL261 intracranial glioma model. In vitro treatment of GL261 cells with JSI-124, a STAT3 inhibitor, reversed highly phosphorylated status of STAT3. Systemic i.p. administration of JSI-124 in glioma-bearing immunocompetent mice, but not athymic mice, resulted in prolonged survival, suggesting a role of adaptive immunity in the antitumor effect. Furthermore, JSI-124 promoted maturation of tumor-infiltrating CD11c+ dendritic cells and activation of tumor-conditioned cytotoxic T cells, enhanced dendritic cells and GL261 production of CXCL-10, a critical chemokine for attraction of Tc1 cells. When i.p. JSI-124 administration was combined with i.v. transfer of Pmel-I mouse-derived type-1 CTLs (Tc1), glioma-bearing mice exhibited prolonged survival compared with i.p. JSI-124 or i.v. Tc1 therapy alone. Flow cytometric analyses of brain infiltrating lymphocytes revealed that JSI-124-treatment enhanced the tumor-homing of i.v. transferred Tc1 cells in a CXCL-10-dependent fashion. Systemic JSI-124 administration also up-regulated serum IL-15 levels, and promoted the persistence of transferred Tc1 in the host. These data suggest that systemic inhibition of STAT3 signaling can reverse the suppressive immunological environment of intracranial tumor bearing mice both systemically and locally, thereby promoting the efficacy of adoptive transfer therapy with Tc1. |
| تدمد: | 1550-6606 0022-1767 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e6295dda83f9eb59bd6b484770aafd19Test https://doi.org/10.4049/jimmunol.180.4.2089Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e6295dda83f9eb59bd6b484770aafd19 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15506606 00221767 |
|---|