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TBK1 as a regulator of autoimmunity and antitumor immunity

Cellular & Molecular Immunology volume 15, pages 743–745 (2018)Cite this article

The study of in vivo functions of TBK1 has been hampered by the lack of a viable animal model, since the conventional TBK1 knockout (KO) mice are embryonic lethal.12 Nevertheless, a number of studies have shown that TBK1 responds to signals from diverse receptors, such as TNF receptor (TNFR) superfamily members, T cell receptor (TCR), B cell receptor (BCR), as well as various PRRs, many of which do not induce IFN-I expression (Figure 1).6,7,13,14 The recent development of TBK1-conditional KO mice has led to the characterization of novel functions of TBK1 in the regulation of adaptive immune responses and homeostasis (Figure 1). TBK1 functions in B cells to negatively regulate noncanonical NF-κB activation by TNFR superfamily members, including CD40 and BAFFR, which involves phosphorylation of the noncanonical NF-κB inducing kinase (NIK) for ubiquitin-dependent degradation.6 This function is crucial for controlling IgA class switching, and mice carrying B cell-specific deletion of TBK1 develop a nephropathy-like disease, characterized by heightened serum IgA concentration and antibody deposition onto kidney glomeruli.6 In T cells, TBK1 controls the steady-state level of AKT, which in turn is important for maintaining T cell homeostasis and preventing abnormal T cell activation.7 Unlike the TAK1-IKK signaling axis,15 TBK1 does not seem to regulate the survival or function of regulatory T cells but rather exerts a cell-intrinsic role to regulate T cell homeostasis.7 TBK1 also has a role in regulating T cell migration to the central nervous system in an autoimmune neuroinflammation model.7 In contrast to TBK1, IKKɛ is dispensable for maintaining T cell homeostasis;7 however, IKKɛ plays a role in negatively regulating T cell responses through inhibiting activation of the transcription factor NFATc1.8

While immune tolerance prevents development of autoimmune diseases, it is also a major obstacle for immune responses against cancer, and breaking immune tolerance has been exploited as an approach to boost anti-tumor immune responses in cancer immunotherapy.20,21 In transplantable murine melanoma and thymoma models, DC-specific deletion of TBK1 causes significantly reduced tumor growth and increased survival rate of the tumor-bearing mice, associated with enhanced T cell activation in draining lymph nodes and effector T cell infiltration into the tumor tissue.10 When the DC-specific TBK1 deficiency is combined with treatment with a blocking antibody of the T cell checkpoint molecule PD-1, it results in a marked synergistic effect in the suppression of tumor growth. This finding is corroborated by a more recent study using an organotypic tumor spheroid technique.11 In this ex vivo approach, pharmacological inhibition of TBK1 and IKKɛ also greatly potentiates the induction of anticancer immunity by PD-1 blockade using an anti-PD-L1 antibody. Moreover, treatment of mice bearing the CT26 colorectal tumor with anti-PD-L1 and TBK1 inhibitor leads to greater tumor control and longer survival than single treatment with either anti-PD-L1 or TBK1 inhibitor.11 Together, these two separate studies demonstrate an important role for TBK1 in regulating antitumor immunity and further emphasize the function of TBK1 in regulating immune tolerance (Figure 2). These findings also suggest the intriguing possibility that targeting TBK1 may be an approach to improve the efficacy of cancer immunotherapy.

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Acknowledgements

Work in the authors’ laboratory is supported by grants from the US National Institutes of Health (AI057555, AI064639, GM84459, and AI104519) and the Cancer Prevention and Research Institute of Texas (RP150235).

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  1. Central Laboratory, Affiliated Hospital of Hebei University, 212 Yuhua East Road, 07100, Baoding, China

    Jian-Hong Shi

  2. Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, 77030, Houston, TX, USA

    Jian-Hong Shi, Xiaoping Xie & Shao-Cong Sun

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Shi, JH., Xie, X. & Sun, SC. TBK1 as a regulator of autoimmunity and antitumor immunity. Cell Mol Immunol 15, 743–745 (2018). https://doi.org/10.1038/cmi.2017.165

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