Interactions of host IL-6 and IFN-γ and cancer-derived TGF-β1 on MHC molecule expression during tumor spontaneous regression
Journal
Cancer Immunology, Immunotherapy
Journal Volume
57
Journal Issue
7
Pages
1091-1104
Date Issued
2008
Author(s)
Abstract
Many tumors down-regulate major histocompatibility complex (MHC) antigen expression to evade host immune surveillance. However, there are very few in vivo models to study MHC antigen expression during tumor spontaneous regression. In addition, the roles of transforming growth factor beta1 (TGF-β1), interferon gamma (IFN-γ), and interleukin (IL)-6 in modulating MHC antigen expression are ill understood. We previously reported that tumor infiltrating lymphocyte (TIL)-derived IL-6 inhibits TGF-β1 and restores natural killing (NK) activity. Using an in vivo canine-transmissible venereal tumor (CTVT) tumor model, we presently assessed IL-6 and TGF-β involvement associated with the MHC antigen expression that is commonly suppressed in cancers. IL-6, IFN-γ, and TGF-β1, closely interacted with each other and modulated MHC antigen expression. In the presence of tumor-derived TGF-β1, host IFN-γ from TIL was not active and, therefore, there was low expression of MHC antigen during tumor progression. TGF-β1-neutralizing antibody restored IFN-γ-activated MHC antigen expression on tumor cells. The addition of exogenous IL-6 that has potent anti-TGF-β1 activity restored IFN-γ activity and promoted MHC antigen expression. IFN-γ and IL-6 in combination acted synergistically to enhance the expression of MHC antigen. Thus, the three cytokines, IL-6, TGF-β1, and IFN-γ, closely interacted to modulate the MHC antigen expression. Furthermore, transcription factors, including STAT-1, STAT-3, IRF-1, NF-κB, and CREB, were significantly elevated after IL-6 and IFN-γ treatment. We conclude that the host IL-6 derived from TIL works in combination with host IFN-γ to enhance MHC molecule expression formerly inhibited by TGF-β1, driving the tumor toward regression. It is suggested that the treatment of cancer cells that constitutively secrete TGF-β1 should incorporate anti-TGF-β activity. The findings in this in vivo tumor regression model have potential applications in cancer immunotherapy. ? 2008 Springer-Verlag.
Subjects
IFN-γ; IL-6; MHC; TGF-β1; Transcription factors
SDGs
Other Subjects
cyclic AMP responsive element binding protein; gamma interferon; immunoglobulin enhancer binding protein; interferon regulatory factor 1; interleukin 6; major histocompatibility antigen; neutralizing antibody; STAT1 protein; STAT3 protein; transforming growth factor beta1; animal cell; animal experiment; animal model; animal tissue; animal venereal tumor; antigen expression; article; cell activity; controlled study; dog; female; immunomodulation; major histocompatibility complex; male; natural killer cell; nonhuman; priority journal; protein expression; protein interaction; tumor associated leukocyte; tumor growth; tumor regression; Animals; Dog Diseases; Dogs; Female; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Interferon Type II; Interleukin-6; Killer Cells, Natural; Lymphocytes, Tumor-Infiltrating; Male; Neoplasm Regression, Spontaneous; Protein Binding; Transforming Growth Factor beta1; Venereal Tumors, Veterinary
Type
journal article