Browsing by Subject "NKG2D"

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    Porcine UL-16 Binding Protein 1 Is Not a Functional Ligand for the Human Natural Killer Cell Activating Receptor NKG2D
    (MDPI, 2023-11-07) Lopez, Kevin J.; Spence, John Paul; Li, Wei; Zhang, Wenjun; Wei, Barry; Cross-Najafi, Arthur A.; Butler, James R.; Cooper, David K. C.; Ekser, Burcin; Li, Ping; Surgery, School of Medicine
    Natural killer (NK) cells play a vital role in xenotransplantation rejection. One approach to induce NK cell immune tolerance is to prevent the NK cell-mediated direct killing of porcine cells by targeting the interaction of the activating receptor NKG2D and its ligands. However, the identity of porcine ligands for the human NKG2D receptor has remained elusive. Previous studies on porcine UL-16 binding protein 1 (pULBP-1) as a ligand for human NKG2D have yielded contradictory results. The goal of the present study was to clarify the role of pULBP-1 in the immune response and its interaction with human NKG2D receptor. To accomplish this, the CRISPR/Cas9 gene editing tool was employed to disrupt the porcine ULBP-1 gene in a 5-gene knockout porcine endothelial cell line (GGTA1, CMAH, β4galNT2, SLA-I α chain, and β-2 microglobulin, 5GKO). A colony with two allele mutations in pULBP-1 was established as a 6-gene knockout pig cell line (6GKO). We found that pULBP-1-deficient pig cells exhibited a reduced binding capacity to human NKG2D-Fc, a recombinant chimera protein. However, the removal of ULBP-1 from porcine endothelial cells did not significantly impact human NK cell degranulation or cytotoxicity upon stimulation with the pig cells. These findings conclusively demonstrate that pULBP-1 is not a crucial ligand for initiating xenogeneic human NK cell activation.
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    Sodium valproate enhances efficacy of NKG2D CAR-T cells against glioblastoma
    (Frontiers Media, 2025-01-14) Liu, Junchen; Dai, Kun; Saliu, Muhammad Auwal; Salisu, Mansur Dabai; Gan, Jiangyu; Afolabi, Lukman Olalekan; Yan, Dehong; Zhang, Guizhong; Liu, Maoxuan; Wan, Xiaochun; Pediatrics, School of Medicine
    Chimeric antigen receptor T-cell (CAR-T) therapies have shown promise in glioblastoma clinical studies, but responses remain inconsistent due to heterogeneous tumor antigen expression and immune evasion post-treatment. NKG2D CAR-T cells have demonstrated a favorable safety profile in patients with hematologic tumors, and showed robust antitumor efficacy in various xenograft models, including glioblastoma. However, malignant glioma cells evade immunological surveillance by reducing NKG2D ligands expression or cleavage. To enhance the effectiveness of NKG2D CAR-T therapy, we investigated the potential of combining NKG2D CAR-T with approved drugs that cross the blood-brain barrier and augment NKG2D ligands expression in glioma cells. We found that sodium valproate (VPA), an antiepileptic drug, significantly increased surface NKG2D ligands expression on glioblastoma cells at a sublethal concentration. VPA treatment enhanced the susceptibility of glioblastoma cells to NKG2D CAR-T mediated cytotoxicity in both 2D monolayer and 3D tumor spheroid models in vitro. Moreover, VPA-treated glioblastoma cells stimulated CAR-T cells to produce higher levels of inflammatory cytokines (IL-2, IFN-γ, and IL-6). Mechanistically, VPA upregulated NKG2D ligands expression via the PI3K/Akt signaling pathway. Additionally, VPA treatment augmented the antitumor activity of NKG2D CAR-T cells in a glioblastoma xenograft model in vivo. These preclinical results suggest that combining VPA with NKG2D CAR-T therapy represents a promising strategy for improving glioblastoma treatment, warranting further clinical investigation.