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Interactions of host IL-6 and IFN-γ and cancer-derived TGF-β1 on MHC molecule expression during tumor spontaneous regression

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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.

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Acknowledgments

This project was supported by National Science Council of Taiwan (NSC95-2313-B-002-375) and Council of Agriculture of Taiwan (96AS-1.2.1-AD.U1(20)).

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Authors and Affiliations

  1. Department of Veterinary Medicine, National Taiwan University, Taipei, Taiwan, ROC

    Ya-Wen Hsiao, Tien-Fu Chung, Chen-Hsuan Liu, Chia-Da Hsu & Rea-Min Chu

  2. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, ROC

    Ya-Wen Hsiao

  3. Department of the Biological Science and Technology, National Chiao Tung University, Hsin-Chu, Taiwan, ROC

    Kuang-Wen Liao

  4. Department of Veterinary Medicine, Animal Cancer Research Center, 1 Roosevelt Road, Section 4, Taipei, 106, Taiwan, ROC

    Rea-Min Chu

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  1. Ya-Wen Hsiao
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Correspondence to Rea-Min Chu.

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Hsiao, YW., Liao, KW., Chung, TF. et al. Interactions of host IL-6 and IFN-γ and cancer-derived TGF-β1 on MHC molecule expression during tumor spontaneous regression. Cancer Immunol Immunother 57, 1091–1104 (2008). https://doi.org/10.1007/s00262-007-0446-5

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