Combined immunogene therapy of IL-6 and IL-15 enhances antitumor activity through augmented NK cytotoxicity.
Resource
Cancer Lett.,277(2),285-295.
Journal
Cancer Letters
Pages
285-295
Date Issued
2009-08
Date
2009-08
Author(s)
Lin, C. Y.
Chuang, T. F.
Liao, K. W.
Huang, Y. J.
Pai, C. C.
Chu, R.M.
Abstract
Many tumors evade host immunity by lowering expression of major histocompatibility complex (MHC) molecules. Theoretically, low MHC expression should activate natural killer (NK) cells and in some cases suppress tumor growth; nevertheless, some tumors also produce high concentrations of immunosuppressive cytokines, such as transforming growth factor (TGF)-β, to inhibit the activity of NK cells. Using a canine transmissible venereal tumor (CTVT) model, we have previously demonstrated that IL-6 is a strong antagonist for TGF-β. Herein, we found that IL-6 alone was unable to significantly promote TGF-β-inhibited NK activities. Conversely, IL-15 alone strongly promoted NK activities; however, NK activities were inhibited to baseline levels following the addition of TGF-β. Therefore, a new strategy using combined immunogene therapy of both IL-6 and IL-15 mediated by electroporation was used in this study. This combined IL-6 and IL-15 treatment effectively relieved the inhibitory effect of TGF-β and activated NK cell cytotoxicity of lymphokine-activated killer (LAK) cells. Similarly, in isolated DX5+ NK cells, only IL-6 and IL-15 in combination significantly overcame the inhibitory effect of TGF-β and promoted NK cytotoxicity. The group of BALB/c mice injected with plasmids with IL-6 and IL-15 genes (pIL-6/pIL-15) had the highest percentages of DX5+ NK cells as compared with either the pIL-6 or pIL-15 groups. Further, in SCID mice inoculated with CTVT, electroporation-mediated delivery of pIL-6/pIL-15 was significantly more efficient in suppressing both tumor establishment and tumor growth as compared with pIL-6 or pIL-15 inoculation alone. In addition, the anti-asialo GM-1 antibody abolished NK activities in SCID mice and resulted in outgrowth of the tumors. Together, these results suggest that the TGF-β-associated inhibition of NK cytotoxicity cannot be adequately restored by simply antagonizing TGF-β with IL-6: the co-existence of NK activating factors such as IL-15 is also important in restoring TGF-β-inhibited cytotoxicity. This study highlights the therapeutic potential of the pIL-6/pIL-15 combination by inhibiting TGF-β activity and enhancing NK cytotoxicity. ? 2008 Elsevier Ireland Ltd. All rights reserved.
Subjects
Electroporation; Gene therapy; Interleukins; NK cytotoxicity
SDGs
Other Subjects
interleukin 15; interleukin 6; major histocompatibility antigen; plasmid DNA; transforming growth factor beta; animal cell; animal experiment; animal model; animal venereal tumor; antineoplastic activity; article; cancer inhibition; controlled study; cytokine production; DNA transfection; effector cell; electroporation; enzyme linked immunosorbent assay; female; flow cytometry; gene expression; gene targeting; gene therapy; lymphokine activated killer cell; mouse; natural killer cell mediated cytotoxicity; nonhuman; priority journal; spleen cell; tumor growth; tumor xenograft; Animals; Combined Modality Therapy; Cytotoxicity, Immunologic; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Gene Therapy; Humans; Immunotherapy; Interleukin-15; Interleukin-6; Killer Cells, Natural; Mice; Mice, Inbred BALB C; Mice, SCID; Neoplasms, Experimental; Mus
Type
journal article