Cutting Edge: Engineering Active IKKβ in T Cells Drives Tumor Rejection

Evaristo, César; Spranger, Stefani; Barnes, Sarah E.; Miller, Michelle L.; Molinero, Luciana; Locke, Frederick L.; Gajewski, Thomas F.; Alegre, Maria‐Luisa

doi:10.4049/jimmunol.1501144

Cited by 23 publications

(19 citation statements)

References 34 publications

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“…2C/Rag2 −/− and P14/Rag2 −/− mice have been previously described ( Brown et al, 2006 ). Egr2 flox/flox mice were a gift from H. Singh (University of Chicago, Chicago, IL), and pLCK-CreERT2 x ROSA-YFP mice were generated in our laboratory and have been previously described ( Evaristo et al, 2016 ). B16.SIY.dsRed ( Kline et al, 2012 ), C1498.SIY.GFP ( Zhang et al, 2009 ), and MC57.SIY.GFP ( Spiotto et al, 2002 ) tumor cells were engineered to express either dsRed or GFP in frame with the H2-K b –restricted model antigen SIYRYYGL.…”

Section: Methodsmentioning

confidence: 99%

The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment

Williams

Horton

Zheng

et al. 2017

Journal of Experimental Medicine

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176

124

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Section: Methodsmentioning

confidence: 99%

The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment

Williams

Horton

Zheng

et al. 2017

Journal of Experimental Medicine

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176

124

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“…On the one hand NF-κB activation in natural killer cells controls expression of cytotoxic mediators such as perforin and granzyme B important for their antitumorigenic activity [86,87]. Activation of the canonical NF-κB pathway in T-cells also increases the amount of tumor-specific IFNγ-producing CD8+ T-cells that account for tumor elimination [88]. Importantly, disruption of the canonical NF-κB pathway in dendritic cells via the immune checkpoint molecule PD1 further results in a decrease of cytokines and expression of co-stimulatory molecules [89].…”

Section: Nf-κb In Hepatocarcinogenesismentioning

confidence: 99%

Context-Dependent Role of NF-κB Signaling in Primary Liver Cancer—from Tumor Development to Therapeutic Implications

Czauderna

Castven

Mahn

et al. 2019

Cancers

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Chronic inflammatory cell death is a major risk factor for the development of diverse cancers including liver cancer. Herein, disruption of the hepatic microenvironment as well as the immune cell composition are major determinants of malignant transformation and progression in hepatocellular carcinomas (HCC). Considerable research efforts have focused on the identification of predisposing factors that promote induction of an oncogenic field effect within the inflammatory liver microenvironment. Among the most prominent factors involved in this so-called inflammation-fibrosis-cancer axis is the NF-κB pathway. The dominant role of this pathway for malignant transformation and progression in HCC is well documented. Pathway activation is significantly linked to poor prognostic traits as well as stemness characteristics, which places modulation of NF-κB signaling in the focus of therapeutic interventions. However, it is well recognized that the mechanistic importance of the pathway for HCC is highly context and cell type dependent. While constitutive pathway activation in an inflammatory etiological background can significantly promote HCC development and progression, absence of NF-κB signaling in differentiated liver cells also significantly enhances liver cancer development. Thus, therapeutic targeting of NF-κB as well as associated family members may not only exert beneficial effects but also negatively impact viability of healthy hepatocytes and/or cholangiocytes, respectively. The review presented here aims to decipher the complexity and paradoxical functions of NF-κB signaling in primary liver and non-parenchymal cells, as well as the induced molecular alterations that drive HCC development and progression with a particular focus on (immune-) therapeutic interventions.

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“…In humans, however, IKKb deletion seems to be less harmful, as homozygous deletion of the IKBKB gene is not lethal, at least in some cases, but leads to immunodeficiency (38). In agreement with the multiple functions of IKKb, its effect on tumoral transformation of the cells can be mediated by different pathways, such as NF-kB activation (39); adaptation to metabolic and oxidative stresses, increasing the ability of cancer cells to survive at low glutamine concentration (40); establishment of stemness properties by Wnt pathway regulation (41); modulation of T-cell-dependent antitumoral immune response (42); or inactivation of important cell-cycle controllers as p53 (2) and p16 (3) among others. As a result of these pleiotropic functions, IKKb promotes cellular transforma-tion and tumor growth in lung, pancreas, and oral epithelia, among others (16,17,19), but it also results in an antitumoral effect in myeloid cells during melanoma tumorigenesis (18).…”

Section: Discussionmentioning

confidence: 93%

IKKβ-Mediated Resistance to Skin Cancer Development Is Ink4a/Arf-Dependent

Page

Bravo

Suárez-Cabrera

et al. 2017

Molecular Cancer Research

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IKKβ (encoded by ) is a protein kinase that regulates the activity of numerous proteins important in several signaling pathways, such as the NF-κB pathway. IKKβ exerts a protumorigenic role in several animal models of lung, hepatic, intestinal, and oral cancer. In addition, genomic and proteomic studies of human tumors also indicate that gene is amplified or overexpressed in multiple tumor types. Here, the relevance of IKKβ in skin cancer was determined by performing carcinogenesis studies in animal models overexpressing IKKβ in the basal skin layer. IKKβ overexpression resulted in a striking resistance to skin cancer development and an increased expression of several tumor suppressor proteins, such as p53, p16, and p19. Mechanistically, this skin tumor-protective role of IKKβ is independent of p53, but dependent on the activity of the locus. Interestingly, in the absence of p16 and p19, IKKβ-increased expression favors the appearance of cutaneous spindle cell-like squamous cell carcinomas, which are highly aggressive tumors. These results reveal that IKKβ activity prevents skin tumor development, and shed light on the complex nature of IKKβ effects on cancer progression, as IKKβ can both promote and prevent carcinogenesis depending on the cell type or molecular context. The ability of IKKβ to promote or prevent carcinogenesis suggests the need for further evaluation when targeting this protein. .

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Cutting Edge: Engineering Active IKKβ in T Cells Drives Tumor Rejection

Cited by 23 publications

References 34 publications

The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment

The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment

Context-Dependent Role of NF-κB Signaling in Primary Liver Cancer—from Tumor Development to Therapeutic Implications

IKKβ-Mediated Resistance to Skin Cancer Development Is Ink4a/Arf-Dependent

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