Potent immunotherapy against well-established thymoma using adoptively transferred transgene IL-6-engineered dendritic cell-stimulated CD8+ T-cells with prolonged survival and enhanced cytotoxicity.

Abstract

BACKGROUND:

Adoptive transfer of CD8(+) T-cells specific for tumor-antigens is an attractive strategy for anti-tumor therapy. In the present study, the subsets TA and TB were used to represent the population of CD8(+) T cells generated by culturing the respective cells with irradiated dendritic cells (DCs) pulsed with ovalbumin (OVA) protein and transfected with adenoviral vector constructs as described.

METHODS:

Naïve OVA specific CD8(+) T cells were isolated from the spleen of OVA-specific T-cell receptor transgenic OTI mice. The subsets TA and TB were then generated by in vitro activating the population of CD8(+) T cells with OVA-pulsed DCs transfected with IL-6-expressing adenoviral vector (AdVIL-6 ) or the control vector (AdVNull ). To assess their in vivo immunotherapeutic effects, TA - or TB -cells were intravenously transferred into C57BL/6 mice bearing EG7 thymoma (6-8 mm in diameter).

RESULTS:

TA -cells displayed a higher level of expression of CD62 l, IL-7R, FasL, perforin and CCR6, and also exhibited more potent in vitro cytotoxicity to OVA-expressing EG7 thymoma cells via perforin- and Fas/FasL-mediated apoptosis than TB -cells. CD8(+) T-cell survival was kinetically analyzed in C57BL/6 mice transferred with TA - or TB -cells by flow cytometry. We found that the adoptively transferred TA -cells had prolonged survival and enhanced T-cell memory development compared to TB -cells. In addition, TA -, but not TB -cells were able to eradicate well-established EG7 thymomas in all eight tumor-bearing mice.

CONCLUSIONS:

Our data suggest that AdVIL-6 -transfected DC-stimulated CD8(+) T cells with potent cytotoxicity and survival advantage may serve as an effective adoptive CD8(+) T-cell immunotherapy strategy for anti-tumor treatment.

• Authors: Kalpana Kalyanasundaram Bhanumathy, Bei Zhang, Yufeng Xie, Aizhang Xu, Xin Tan, Jim Xiang
• Journal: The journal of gene medicine (J Gene Med) 2015 Aug-Sep Vol. 17 Issue 8-9 Pg. 153-60 ISSN: 1521-2254 [Electronic] England
• PMID: 26212685 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 John Wiley & Sons, Ltd.

Chemical References

• Antigens, Neoplasm
• Interleukin-6

Topics

• Adenoviridae (genetics)
• Animals
• Antigens, Neoplasm (immunology)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Cell Line, Tumor
• Cell Survival
• Cytotoxicity, Immunologic
• Dendritic Cells (immunology, metabolism)
• Disease Models, Animal
• Genetic Vectors (genetics)
• Immunotherapy, Adoptive
• Interleukin-6 (genetics)
• Lymphocyte Activation
• Mice
• Mice, Transgenic
• Phenotype
• T-Lymphocyte Subsets (immunology, metabolism)
• Thymoma (genetics, immunology, therapy)
• Transgenes (genetics)