The kinase TBK1 functions in dendritic cells to regulate T cell homeostasis, autoimmunity, and antitumor immunity

Xiao, Yichuan; Zou, Qiang; Xie, Xiaoping; Liu, Ting; Li, Haiyan S.; Jie, Zuliang; Jin, Jin; Hu, Hongbo; Manyam, Ganiraju C.; Zhang, Li; Cheng, Xuhong; Wang, Hui; Marié, Isabelle; Levy, David E.; Watowich, Stephanie S.; Sun, Shao Cong

doi:10.1084/jem.20161524

Cited by 65 publications

(69 citation statements)

References 46 publications

(82 reference statements)

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“…An important consideration with our Tbk1 Δ/Δ PDA models is that the global Tbk1 mutation eliminates TBK1 kinase activity and significantly reduces Tbk1 expression in all cell types, including immune cells, which could impact immune responses to tumor challenge. In fact, a recent study demonstrated that dendritic cell conditional Tbk1 knockout mice (Tbk1-DKO) injected subcutaneously with B16 melanoma cells lived longer and had smaller tumors compared to wild-type Tbk1 control mice [46]. An assessment of B16 melanoma tumors from Tbk1-DKO animals revealed enhanced interferon-responsive gene expression and greater T-effector cell infiltration into tumors and lymph nodes, confirming antitumor immunity conferred by dendritic cell Tbk1 loss.…”

Section: Discussionmentioning

confidence: 94%

“…TBK1 is central to numerous biological processes that could affect the growth of the primary tumor, including cell division, autophagy, innate immune response, and AKT/mTOR signaling [26,40,41,[44][45][46][47][48][49]. In the context of pancreatic cancer, TBK1 has been reported to promote basal levels of autophagy as a means of silencing cytokine production [48].…”

Section: Discussionmentioning

confidence: 99%

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Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer

Cruz

Arner

et al. 2018

Preprint

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Pancreatic ductal adenocarcinoma (PDA) is characterized by an activating mutation in KRAS, which is critical for the biology of PDA progression. Direct inhibition of KRAS through pharmacological means remains a challenge; however, targeting key KRAS effectors has therapeutic potential. We investigated the contribution of TANK-binding kinase 1 (TBK1), a critical downstream effector of mutant active KRAS, to PDA progression. We report that higher levels of TBK1 mRNA are associated with poorer overall survival in human PDA patients and that TBK1 supports the growth and metastasis of KRAS-mutant PDA by driving an epithelial plasticity program in tumor cells that enhances invasive and metastatic capacity. Further, we identify that the receptor tyrosine kinase Axl induces TBK1 activity in a Ras-RalB-dependent manner.These findings demonstrate that TBK1 is central to an Axl-driven epithelialmesenchymal transition in KRAS-mutant PDA and suggest that interruption of the Axl-TBK1 signaling cascade above or below KRAS has potential therapeutic efficacy in this recalcitrant disease.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer

Cruz

Arner

et al. 2018

Preprint

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“…regulates the homeostasis of immunity [13][14][15] . David R Beers and Stanley H Appel deeply reviewed the immune dysregulation in ALS and suggested that targeting the immune system could provide therapeutic strategies to ameliorate the pathogenesis of ALS [20] .…”

Section: Discussionmentioning

confidence: 99%

“…Tbk1 germline knockout (KO) mice die embryonically at E14.5 due to liver degeneration [12] . The recent generation of Tbk1 conditional KO mice has demonstrated that Tbk1 maintains the immune balance in the body [13][14][15] . Our previous study demonstrated that Tbk1 deletion in neuron progenitor cells caused mild cognitive and locomotor de cits [16] .…”

Section: Introductionmentioning

confidence: 99%

Motor injury is caused by TBK1 deficiency in the myeloid cell and rescued by PEI-manose-TBK1

Duan¹,

Le²,

Tian³

et al. 2020

Preprint

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Background: TBK1 haploinsufficiency has been shown to cause both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); however, the mechanism is unclear. Methods: A myeloid Tbk1 knockout mice (Tbk1-LKO mice) was established. Motor functional and pathological analyses were also performed. The p-TBK1 was tested by flow cytometry in the ALS animal model and patients. The inflammatory proteins and mRNA was analyzed by Western blot and RT-PCR.Results: We found that the latency to fall in seven-month-old Tbk1-LKO mice was significantly reduced on evaluation on two consecutive days. Overall, 25.6% of Tbk1-LKO mice presented paralysis symptoms and signs along with a loosened myelin sheath and axon degeneration at 14-16 months of age. Furthermore, Tbk1 deficiency in myeloid cells induced inflammatory cell infiltration and dysbacteriosis in the digestive tract. Additionally, p-Tbk1 content was reduced by 29.5% and 14.8% in monocytes of definite ALS and probable ALS patients and decreased by 27.6% and 45.5% in the monocytes and microglia of ALS animals, respectively. PEI-mannose-TBK1 or PEI-mannose-SaCas9-sgRNA for deleting mutant SOD1 in macrophages significantly delayed disease onset and prolonged survival in the ALS mouse model. Conclusions: These data suggest that inflammatory monocyte and macrophage infiltration and impaired innate immune defense are contributing factors to ALS and FTD.

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“…It is, however, worth noting that TBK1 is expressed in various cell types in the tumor microenvironment and not only in the actual cancer cells. For example, a recent report shows that TBK1 deletion specifically in dendritic cells results in enhanced T-cell activity and antitumor immunity (42). Furthermore, TBK1 was suggested to mediate proangiogenic signals and could contribute to early malignant progression and tumor cell survival by promoting vessel formation (14,16,17).…”

Section: Discussionmentioning

confidence: 99%

TANK‐binding kinase 1 is a mediator of platelet‐induced EMT in mammary carcinoma cells

et al. 2019

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Platelets can promote several stages of the metastatic process and thus contribute to malignant progression. As an example, platelets promote invasive properties of tumor cells by induction of epithelial to mesenchymal transition (EMT). In this study, we show that tumor necrosis factor receptor‐associated factor (TRAF) family member‐associated NF‐κB activator (TANK)‐binding kinase 1 (TBK1) is a previously unknown mediator of platelet‐induced EMT in mammary carcinoma cells. Coculture of 2 mammary carcinoma cell lines, Ep5 from mice and MCF10A(MII) from humans, with isolated platelets induced morphologic as well as molecular changes characteristic of EMT, which was paralleled with activation of TBK1. TBK1 depletion using small interfering RNA impaired platelet‐induced EMT in both Ep5 and MCF10A(MII) cells. Furthermore, platelet‐induced activation of the NF‐κB subunit p65 was suppressed after TBK1 knockdown, demonstrating that TBK1 mediates platelet‐induced NF‐κB signaling and EMT. Using an in vivo metastasis assay, we found that depletion of TBK1 from mammary carcinoma cells during in vitro preconditioning with platelets subsequently suppressed the formation of lung metastases in mice. Altogether, these results suggest that TBK1 contributes to tumor invasiveness and may be a driver of metastatic spread in breast cancer.—Zhang, Y., Unnithan, R. V. M., Hamidi, A., Caja, L., Saupe, F., Moustakas, A., Cedervall, J., Olsson, A.‐K. TANK‐binding kinase 1 is a mediator of platelet‐induced EMT in mammary carcinoma cells. FASEB J. 33, 7822–7832 (2019). http://www.fasebj.org

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The kinase TBK1 functions in dendritic cells to regulate T cell homeostasis, autoimmunity, and antitumor immunity

Abstract: Xiao et al. demonstrate that a protein kinase, TBK1, regulates the function of dendritic cells in mediating immune responses.

Cited by 65 publications

References 46 publications

Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer

Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer

Motor injury is caused by TBK1 deficiency in the myeloid cell and rescued by PEI-manose-TBK1

TANK‐binding kinase 1 is a mediator of platelet‐induced EMT in mammary carcinoma cells

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