Regulation of NKG2D Stress Ligands and Its Relevance in Cancer Progression

Friedman, Gregory K.

doi:10.3390/cancers14092339

Cited by 23 publications

(18 citation statements)

References 241 publications

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“…In this study, our results suggested that CD122 + NKG2D + bystander-activated CD8 + T cells could produce abundant granzyme B and perforin ( Supplementary Figures 1 , 2 ). Indeed, NKG2D can directly bind to a diverse family of ligands on the surface of target cells, thereby resulting in the activation or synergistic stimulation of immune effectors and subsequently release of cytolytic molecules ( Jones et al., 2022 ). Thus, NKG2D + cells might be positive totally for the expression of granzyme and perforin.…”

Section: Discussionmentioning

confidence: 99%

IL-15 induced bystander activation of CD8+ T cells may mediate endothelium injury through NKG2D in Hantaan virus infection

Zhang

et al. 2022

Front. Cell. Infect. Microbiol.

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IntroductionHantaan virus (HTNV) can cause endothelium injury in hemorrhagic fever with renal syndrome (HFRS) patients. Bystander activation of CD8+ T cells by virus infection has been shown that was involved in host injury, but it is unclear during HTNV infection. This project aimed to study the effect of bystander-activated CD8+ T cell responses in HTNV infection.MethodsThe in vitro infection model was established to imitate the injury of endothelium in HFRS patients. Flow cytometry was performed to detect the expression of markers of tetramer+ CD8+ T cells and human umbilical vein endothelial cells (HUVECs). The levels of interleukin-15 (IL-15) in serum and supermanant were detected using ELISA kit. The expression of MICA of HUVECs was respectively determined by flow cytometry and western blot. The cytotoxicity of CD8+ T cells was assessed through the cytotoxicity assay and antibody blocking assay.ResultsEBV or CMV-specific CD8+ T cells were bystander activated after HTNV infection in HFRS patients. HTNV-infected HUVECs in vitro could produce high levels of IL-15, which was positively correlated with disease severity and the expression of NKG2D on bystander-activated CD8+ T cells. Moreover, the elevated IL-15 could induce activation of CD122 (IL-15Rβ)+NKG2D+ EBV/CMV-specific CD8+ T cells. The expression of IL-15Rα and ligand for NKG2D were upregulated on HTNV-infected HUVECs. Bystander-activated CD8+ T cells could exert cytotoxicity effects against HTNV-infected HUVECs, which could be enhanced by IL-15 stimulation and blocked by NKG2D antibody.DiscussionIL-15 induced bystander activation of CD8+ T cells through NKG2D, which may mediate endothelium injury during HTNV infection in HFRS patients.

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Section: Discussionmentioning

confidence: 99%

IL-15 induced bystander activation of CD8+ T cells may mediate endothelium injury through NKG2D in Hantaan virus infection

Zhang

et al. 2022

Front. Cell. Infect. Microbiol.

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“…One approach entails the engagement of ligand families that are commonly dysregulated in cancer, such as the eight NKG2D ligands. These ligands are upregulated by cell stress events such as DNA damage that are highly prevalent in transformed cells 6 . Accordingly, it is estimated that at least 80% of human cancers express these ligands 7–12 .…”

Section: Target Selectionmentioning

confidence: 99%

Solid tumours: Building bridges to CAR‐T success

Maher

2023

Clinical and Translational Dis

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In contrast to blood cancers, solid tumours have largely proven refractory to CAR-based immunotherapy. Obstacles include the lack of tumour-specific targets, difficulty in entry and infiltration of tumour deposits and the myriad of immunosuppressive factors that operate within the tumour microenvironment. We also consider various host cell types for CAR engineering that have been proposed as alternatives to conventional T-cells.

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“…NKG2D (encoded by the killer cell lectin-like receptor subfamily K, member 1, or KLRK1 gene) is a C-type lectin receptor and a major activating immunoreceptor involved in tumor immune surveillance. NKG2D is expressed on the surface of most cytotoxic lymphocytes such as Natural killer (NK) cells, CD8+ T cells, some γδ T cells, and possibly also on some CD4+ T cells and is known as a sensor for damaged or dangerous cells [ 1 , 2 ]. Ligands for NKG2D are generally not expressed on healthy cells but are induced on the surface of malignant cells.…”

Section: Introductionmentioning

confidence: 99%

“…It has been previously described that the transcriptional upregulation of NKG2D-L mainly depends on the activation of cellular stress signals, although the specific molecular mechanisms remain largely unknown. In general, inducible expression of NKG2D-L is observed in response to oncogenic transformation, cell cycle alterations, and DNA damage [ 1 ]. NKG2D-L induction in mice was attributed to a hyperproliferative state which activates the E2F transcription factor and p53, allowing the transcription of NKG2D-L.…”

Section: Introductionmentioning

confidence: 99%

KLF4-mediated upregulation of the NKG2D ligand MICA in acute myeloid leukemia: a novel therapeutic target identified by enChIP

et al. 2023

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The immunoreceptor NKG2D, which is expressed on NK cells and T cell subsets is critically involved in tumor immune surveillance. This applies in particular to acute myeloid leukemia (AML), which evades immune detection by downregulation of NKG2D ligands (NKG2D-L), including MICA. The absence of NKG2D-L on AML cells is moreover associated with leukemia stem cell characteristics. The NKG2D/NKG2D-L system thus qualifies as an interesting and promising therapeutic target.Here we aimed to identify transcription factors susceptible to pharmacological stimulation resulting in the expression of the NKG2D-L MICA in AML cells to restore anti-tumor activity. Using a CRISPR-based engineered ChIP (enChIP) assay for the MICA promoter region and readout by mass spectrometry-based proteomics, we identified the transcription factor krüppel-like factor 4 (KLF4) as associated with the promoter. We demonstrated that the MICA promoter comprises functional binding sites for KLF4 and genetic as well as pharmacological gain- and loss-of-function experiments revealed inducible MICA expression to be mediated by KLF4.Furthermore, induction in AML cells was achieved with the small compound APTO253, a KLF4 activator, which also inhibits MYC expression and causes DNA damage. This induction in turn yielded increased expression and cell surface presentation of MICA, thus rendering AML cells more susceptible to NK cell-mediated killing. These data unravel a novel link between APTO253 and the innate anti-tumor immune response providing a rationale for targeting AML cells via APTO253-dependent KFL4/MICA induction to allow elimination by endogenous or transplanted NK and T cells in vivo.

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Regulation of NKG2D Stress Ligands and Its Relevance in Cancer Progression

Cited by 23 publications

References 241 publications

IL-15 induced bystander activation of CD8+ T cells may mediate endothelium injury through NKG2D in Hantaan virus infection

IL-15 induced bystander activation of CD8+ T cells may mediate endothelium injury through NKG2D in Hantaan virus infection

Solid tumours: Building bridges to CAR‐T success

KLF4-mediated upregulation of the NKG2D ligand MICA in acute myeloid leukemia: a novel therapeutic target identified by enChIP

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