What Inhibits Natural Killers’ Performance in Tumour

Papak, Ines; Chruściel, Elżbieta; Dziubek, Katarzyna; Kurkowiak, Małgorzata; Urban-Wójciuk, Zuzanna; Marjański, Tomasz; Rzyman, Witold; Marek-Trzonkowska, Natalia

doi:10.3390/ijms23137030

Cited by 6 publications

(1 citation statement)

References 217 publications

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“…However, targeting specific antigens in NSCLC with engineered CAR-T cells was complex due to the shortage of tumor-specific antigens, immunosuppressive tumor microenvironment, low levels of CAR-T cell invasion into tumor tissue, and tumor antigen escape [17]. NK cells are known to be "serial killers" with NK and NK-92 cells (the cell line approved by the Food and Drug Administration as the first NK cell-based immunotherapy for clinical trials [18]) and one NK cell can kill up to 7-10 tumor cells [19,20]. Therefore, we hypothesized that the construction of FAP-targeting CAR-NK cells might contribute to the treatment of NSCLC.…”

Section: Introductionmentioning

confidence: 99%

Development of FAP-Targeted Chimeric Antigen Receptor NK-92 Cells for Non-Small Cell Lung Cancer

Yang¹,

Wang²,

Zhao³

et al. 2023

Discovery Medicine

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Objectives: Over the past two decades, great progress has been made in advancing the early detection and multimodal treatment of non-small cell lung cancer (NSCLC). However, overall cure rates and survival rates of NSCLC are still not satisfactory, and research into new therapies is needed. This study attempted to construct human Fibroblast Activation Protein-Chimeric Antigen Receptor Natural killer (NK)-92 cells (hFAP-CAR-NK-92 cells) and explore their potential therapeutic effects in NSCLC. Methods: Immunohistochemistry analysis was carried out to examine fibroblast activation protein (FAP) and Gasdermin E (GSDME) expression in clinical specimens of lung adenocarcinoma and squamous cell carcinoma tissue. Then the engineered hFAP-CAR-NK-92 cells efficiency was determined in vitro with lactate dehydrogenase (LDH) cytotoxicity assay and the cell morphology of A549, H226, and cancer-related fibroblast (CAF) was observed by electron microscopy. After the co-culture of target cells and effect cells, flow cytometry was employed for examining the CD107a expression in the effect cells, and western blotting was conducted for the cleavage levels of Caspase 3 and GSDME proteins in the target cells. The safety and efficacy of hFAP-CAR-NK-92 cells adoptive transfer immunotherapy in a tumor-bearing mouse were evaluated. Results: Clinical studies have shown FAP positivity in patients with NSCLC. Compared with A549 or H226 cells alone, FAP expression was notably raised in A549+CAF cells or H226+CAF cells in nude mice, respectively (p < 0.05). The killing efficiency of K562 cells was not significantly different between hFAP-CAR-NK-92 and NK-92 cells (p > 0.05). The hFAP-CAR-NK-92 cells presented a higher killing efficiency against the hFAP-target (A549-hFAP, H226-hFAP and CAF-hFAP) cells than the NK-92 cells (p < 0.05). The degranulation of CD107a and cleavage levels of GSDME and Caspase 3 protein in the hFAP-CAR-NK-92 group were higher than those in the NK-92 group (p < 0.05). The 300 nM Granzyme B also induced pyroptosis in hFAP-or GSDMEpositive cells (p < 0.05). In vivo experiments revealed that hFAP-CAR-NK-92 cells inhibited tumor progression of hFAP-positive NSCLC (p < 0.05). Conclusions: In this study, we successfully constructed hFAP-CAR-NK-92 cells and confirmed that hFAP-CAR-NK-92 cells could target hFAP-positive NSCLC to inhibit the progression of NSCLC by activating the Caspase-3/GSDME pyroptosis pathway.

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Section: Introductionmentioning

confidence: 99%

Development of FAP-Targeted Chimeric Antigen Receptor NK-92 Cells for Non-Small Cell Lung Cancer

Yang¹,

Wang²,

Zhao³

et al. 2023

Discovery Medicine

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Evaluating Predictors of Quality in Liver NK Cells Among Deceased Donors

Imaoka,

Ohira,

Nakayama

et al. 2024

Cell Transplant

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This study investigated the substantial variability in the quality of liver natural killer (NK) cells from deceased donors (DDs). This study assessed liver nonparenchymal cells from 51 DDs for activation receptors and cytotoxicity against K562 (leukemia) and HepG2 (hepatoma) cell lines. The results indicated variability in TNF-related apoptosis-inducing ligand (TRAIL) and NK stimulatory receptor NK group 2 member D (NKG2D) expression in liver NK cells from DDs, which correlated with cytotoxicity against tumor cell lines. In addition, the white blood cell (WBC) count, aspartate aminotransferase (AST) level, body mass index (BMI), and platelet count were significantly associated with enhanced TRAIL and NKG2D expression. A predictive score integrating AST/platelet ratio index, BMI, and WBC count was developed to effectively identify DDs with high antitumor activity in liver NK cells. This score is expected to predict DDs with high-quality liver NK cells, which can be used for the purpose of immunotherapies.

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M1/M2 macrophages: origin, phenotype, methods of production, interaction with natural killer cells and trophoblast

Zhguleva,

Zementova,

Selkov

et al. 2024

Med. immunol.

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This review presents current data on the origin of monocytes/macrophages, the conditions necessary for the differentiation of monocytes into M1 or M2 macrophages. Three subpopulations of peripheral blood monocytes are described: (I) classical – the main subpopulation (85-90%), effectively carrying out phagocytosis; (II) intermediate monocytes (5-10%) – participate in antigen processing and presentation, in angiogenesis, vascular endothelium restoration; (III) non-classical monocytes (10%) - "patrol" vascular network, remove cellular debris, participate in tissue remodeling. The review provides detailed characteristics for each subclass of macrophages: pro-inflammatory (M1) and anti-inflammatory (M2), which play different roles in the initiation and resolution of inflammation; their phenotype, the spectrum of secreted cytokines, the expression of transcription factors, and the functions performed are described. For the M2 population, the features of the subpopulation are described in detail: M2a, M2b, M2c, M2d. The review presents methods and approaches to obtaining polarized macrophages in vitro from both peripheral blood monocytes and cells of transplanted cultures based on signals received by macrophages in vivo; the phenotype, cytokine production and functional properties of artificially polarized macrophages depending on the conditions of their production are given. The review examines in detail the features of contact and distant interaction of macrophages of various subclasses with microenvironment cells on the example of natural killer cells and trophoblast cells, provides information on changes in the phenotype, transcriptional and secretory profile of interacting cells. The mechanisms of trophoblast control of macrophage differentiation into a unique M2 population of decidual macrophages controlling both the development and functioning of the trophoblast and its apoptosis are described. The review examines in detail the currently known variants of the interaction of macrophage subpopulations with natural killers. The influence of Mf on NK cells manifests itself in a change in the expression of transcription factors by the latter, which determine not only their differentiation, but also their functional activity. Macrophages are considered as cells that actively influence the functional state and differentiation of natural killers. The review examines the mechanisms of the relationship of all three types of cells: macrophages, trophoblast and natural killers in the area of uteroplacental contact. The study of the interactions of these cells will shed light not only on the features of intercellular relationships in the area of uteroplacental contact, but also on the relationship of tumor cells with NK cells and macrophages.

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What Inhibits Natural Killers’ Performance in Tumour

Cited by 6 publications

References 217 publications

Development of FAP-Targeted Chimeric Antigen Receptor NK-92 Cells for Non-Small Cell Lung Cancer

Development of FAP-Targeted Chimeric Antigen Receptor NK-92 Cells for Non-Small Cell Lung Cancer

Evaluating Predictors of Quality in Liver NK Cells Among Deceased Donors

M1/M2 macrophages: origin, phenotype, methods of production, interaction with natural killer cells and trophoblast

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