Deciphering the transcription factors that regulate the NKG2D ligand MICA in cancer cells
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Philipps-Universität Marburg
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Abstract
Natural Killer (NK) cells constitute a significant part of the innate immune system that show spontaneous cytolytic activity against tumor cells. Their function is tightly regulated by a variety of inhibitory and activating receptors. NKG2D is one of the most prominent activating receptors. Ligands for NKG2D (NKG2D-Ls), such as MHC class I polypeptide-related sequence A (MICA), are generally induced on the surface of malignant cells. However, tumor cells develop mechanisms to evade innate immune surveillance. The mechanisms include down-regulation of ligand expression, proteolytic shedding, and release of soluble NKG2D-L to render the target cells invisible for the NKG2D-dependent NK cell activity. Previously we showed that the treatment with the histone deacetylase inhibitor (HDACi) LBH589 upregulates the expression of NKG2D-L in mouse and human cells.
Nevertheless, the mechanisms regulating NKG2D-L expression upon LBH589 treatment remain elusive. To gain insight into the complex regulation of NKG2D-L MICA promoter on a chromatin level, a CRISPR/dCas9 system-based chromatin immunoprecipitation (enChIP) in combination with mass spectrometry was established as a powerful novel method for identifying DNA-binding molecules. As a result, I could identify, among others, the zinc finger transcription factor KLF4, which can act either as an oncogene or as a tumor suppressor in different cancers depending on the tumor types or stages. Genetic/pharmacological gain and loss of function experiments in acute myeloid leukemia (AML) cells revealed that the inducible MICA expression was associated with the expression of KLF4. Notably, the phase 1 clinical-stage molecule APTO253, known to promote cell cycle arrest and apoptosis, induces the expression of KLF4 in AML cells. This induction was associated with an increased expression of NKG2D-L, thus rendering resistant AML cell lines susceptible to NK cell-mediated killing. These findings shed light on a strong rationale for targeting AML patients by KLF4 induction, using APTO253 in combination with adoptive NK cell transfer to eliminate AML blasts.
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Created: 2023Issued: 2023-05-02Updated: 2023-05-03
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
eng
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DoctoralThesis
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570
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Al khayer, Reem: Deciphering the transcription factors that regulate the NKG2D ligand MICA in cancer cells. : Philipps-Universität Marburg 2023-05-02. DOI: https://doi.org/10.17192/z2023.0333.