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A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell–mediated suppression

Nature Medicine volume 14, pages 258–265 (2008)Cite this article

Abstract

Regulatory T cells (Treg cells) suppress autoreactive immune responses and limit the efficacy of tumor vaccines; however, it remains a challenge to selectively eliminate or inhibit Treg cells. In this study, the zinc-finger A20, a negative regulator of the Toll-like receptor and tumor necrosis factor receptor signaling pathways, was found to play a crucial part in controlling the maturation, cytokine production and immunostimulatory potency of dendritic cells (DCs). A20-silenced DCs showed spontaneous and enhanced expression of costimulatory molecules and proinflammatory cytokines and had different effects on T cell subsets: they inhibited Treg cells and hyperactivated tumor-infiltrating cytotoxic T lymphocytes and T helper cells that produced interleukin-6 and tumor necrosis factor-α and were refractory to Treg cell–mediated suppression. Hence, this study identifies A20 as an antigen presentation attenuator in control of antitumor immune responses during both the priming and the effector phases and provides a strategy to overcome Treg cell–mediated suppression in an antigen-specific manner, reducing the need to directly target Treg cells.

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Figure 1: A20 controls the maturation and cytokine production of DCs.
Figure 2: A20 negatively regulates the immunostimulatory potency of DCs.
Figure 3: Comparison of antitumor activity of siA20-DCs with CD25-specific antibody treatment.
Figure 4: Comparison of antitumor activity of siA20-DCs with that of siS1-DCs (siS1).
Figure 5: Contrasting effects of siA20-DCs on CTLs and Treg cells.
Figure 6: Effects of siA20-DCs on effector T cells.

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Acknowledgements

We thank R. Dutton at the Trudeau Institute for the B6-OVA melanoma cell line. We thank B. Hong, B. Liu, M. Aldrich, N. Lapteva, and A. Sharabi in the lab for technical assistance and valuable suggestions. We also thank M. Brenner, H. Heslop, C. Rooney, R.F. Wang and other colleagues for helpful suggestions and assistance. This work was supported by grants from the US National Institutes of Health (R01CA90427, R01CA116677 and R01AI68472 to S.-Y.C. and R01 CA100841 to X.F.H.), and the Leukemia and Lymphoma Society Specialized Center of Research Program.

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Author notes

  1. Xiao-Tong Song and Kevin Evel Kabler: These authors contributed equally to this study.

Authors and Affiliations

  1. Center for Cell and Gene Therapy, Baylor College of Medicine (BCM), One Baylor Plaza, Houston, 77030, Texas, USA

    Xiao-Tong Song, Kevin Evel Kabler, Lei Shen, Lisa Rollins, Xue F Huang & Si-Yi Chen

  2. Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California (USC), 1450 Biggy Street, Los Angeles, 90033, California, USA

    Xue F Huang & Si-Yi Chen

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Contributions

X.-T.S. and K.E.-K. designed and performed in vitro and in vivo experiments. L.S., L.R. and X.F.H. performed in vitro and in vivo experiments. S.-Y.C. designed this study, supervised this project and wrote the paper.

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Correspondence to Si-Yi Chen.

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Competing interests

S.-Y.C. has an equity interest in ImmunoVac, Inc., which licensed this technology of the modulation of negative immune regulators and applications for immunotherapy.

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Song, XT., Kabler, K., Shen, L. et al. A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell–mediated suppression. Nat Med 14, 258–265 (2008). https://doi.org/10.1038/nm1721

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