Treatment-Enhanced CD4+Foxp3+ Glucocorticoid-Induced TNF Receptor Family RelatedHigh Regulatory Tumor-Infiltrating T Cells Limit the Effectiveness of Cytokine-Based Immunotherapy
| Autor: | Jian Huang, Aklile Berhanu, Hideho Okada, Walter J. Storkus, Simon C. Watkins |
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| Rok vydání: | 2007 |
| Předmět: |
Antigens
Differentiation T-Lymphocyte T cell Immunology chemical and pharmacologic phenomena CD8-Positive T-Lymphocytes Biology Lymphocyte Activation T-Lymphocytes Regulatory Inducible T-Cell Co-Stimulator Protein Mice Interleukin 21 Lymphocytes Tumor-Infiltrating Antigen Antigens CD Cell Line Tumor Glucocorticoid-Induced TNFR-Related Protein medicine Animals Immunology and Allergy Cytotoxic T cell IL-2 receptor Cell Proliferation Mice Inbred BALB C ZAP70 Membrane Proteins FOXP3 Forkhead Transcription Factors hemic and immune systems Neoplasms Experimental medicine.anatomical_structure Cancer research Cytokines Immunotherapy Immunologic Memory CD8 Signal Transduction |
| Zdroj: | The Journal of Immunology. 178:3400-3408 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Regulatory T cells can suppress activated CD4+ and CD8+ T effector cells and may serve as an impediment to spontaneous or therapeutic type 1 antitumor immunity. In a previous study, we observed minimal therapeutic impact, but significantly enhanced T cell cross-priming and lesional infiltration of tumor-reactive CD8+ T cells into established CMS4 sarcomas after combined treatment of BALB/c mice with rFLt3 ligand (rFL) and recombinant GM-CSF (rGM-CSF). In this study, we show that this cytokine regimen also results in the profound enhancement of CD4+ tumor-infiltrating lymphocytes (TIL) expressing FoxP3, IL-10, and TGF-β mRNA, with 50 or 90% of CD4+ TIL coexpressing the CD25 and glucocorticoid-induced TNFR family related molecules, respectively. Intracellular staining for Foxp3 protein revealed that combined treatment with rFL plus rGM-CSF results in a significant increase in CD4+Foxp3+ T cells in the spleen of both control and tumor-bearing mice, and that nearly half of CD4+ TIL expressed this marker. In addition, CD4+ TIL cells were of an activated/memory (ICOShighCD62LlowCD45RBlow) phenotype and were capable of suppressing allospecific T cell proliferation and IFN-γ production from (in vivo cross-primed) anti-CMS4 CD8+ T cells in vitro, via a mechanism at least partially dependent on IL-10 and TGF-β. Importantly, in vivo depletion of CD4+ T cells resulted in the ability of previously ineffective, rFL plus rGM-CSF therapy-induced CD8+ T cells to now mediate tumor regression. |
| Databáze: | OpenAIRE |
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