Enhanced Calcium Signal Induces NK Cell Degranulation but Inhibits Its Cytotoxic Activity

Li, Yang; Yu, Minghang; Yin, Jie; Han, Yanping; Wang, Xi

doi:10.4049/jimmunol.2001141

Cited by 6 publications

(5 citation statements)

References 38 publications

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“…It is possible that a similar behavior could be observed in ex vivo expanded NK cells, wherein NK cells with the highest proliferative potential and a less mature phenotype will have better persistence and overall efficacy in vivo. The current study did not address the relationship between degranulation and cytotoxicity, which could be complex; for instance, it was shown that enhanced calcium signaling induces NK cell degranulation but inhibits cytotoxicity (Li et al, 2022). NK cells may also exhibit a fast granzyme‐mediated killing and switch to a slow death receptor‐mediated killing during subsequent tumor cell encounters (Prager et al, 2019).…”

Section: Discussionmentioning

confidence: 96%

Differential effects on natural killer cell production by membrane‐bound cytokine stimulations

Chang

Tang

Nelson

et al. 2022

Biotech & Bioengineering

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Robust manufacturing production of natural killer (NK) cells has been challenging in allogeneic NK cell-based therapy. Here, we compared the impact of cytokines on NK cell expansion by developing recombinant K562 feeder cell lines expressing membrane-bound cytokines, mIL15, mIL21, and 41BBL, individually or in combination. We found that 41BBL played a dominant role in promoting up to 500,000-fold of NK cell expansion after a 21-day culture process without inducing exhaustion.However, 41BBL stimulation reduced the overall cytotoxic activity of NK cells when combined with mIL15 and/or mIL21. Additionally, long-term stimulation with mIL15 and/or mIL21, but not 41BBL, increased CD56 expression and the CD56 bright population, which is unexpectedly correlated with NK cell cytotoxicity. By conducting single-cell sequencing, we identified distinct subpopulations of NK cells induced by different cytokines, including an adaptive-like CD56 bright CD16 -CD49a + subset induced by mIL15. Through gene expression analysis, we found that different cytokines modulated signaling pathways and target genes involved in cell cycle, senescence, self-renewal, migration, and maturation in different ways. Together, our study demonstrates that cytokine signaling pathways play distinct roles in NK cell

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Section: Discussionmentioning

confidence: 96%

Differential effects on natural killer cell production by membrane‐bound cytokine stimulations

Chang

Tang

Nelson

et al. 2022

Biotech & Bioengineering

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“…To test the ability of PD-L1-pHLIP in combination with avelumab to trigger NK cytotoxicity, two scenarios, namely plate-coated and mircobeads-coupled, were exploited. In addition, CD107a (a biomarker of NK degranulation following cytotoxicity was induced) and IFN-γ (a major proinflammatory mediator released by activated NK cells) as key parameters of antigen/mAb-triggered ADCC function [ [20] , [21] , [22] ], were detected in our system. As a result, plate-coated immobile PD-L1-pHLIP plus avelumab actively stimulated significantly increased expression of CD107a as well as IFN-γ in NK cells compared with control protein plus avelumab or PD-L1-pHLIP plus IgG1 isotype, in a dose-dependent manner ( Fig.…”

Section: Resultsmentioning

confidence: 99%

pHLIP-fused PD-L1 engages avelumab to elicit NK cytotoxicity under acidic conditions

Feng,

Zheng,

Zhang

et al. 2024

Heliyon

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“…Another study has provided evidence that the inhibition of NK cell clustering could downregulate the IFN-γ secretion ability of NK cells [38]. Furthermore, the defects in 2B4 (CD244)/CD48 led to a decrease in intracellular calcium release, which could impede perforin assembly and the exocytosis of soluble granules [35,39,40]. As such, IFN-γ is a representative indicator to evaluate the activation and priming of NK cells.…”

Section: Discussionmentioning

confidence: 99%

Networked Cluster Formation via Trigonal Lipid Modules for Augmented Ex Vivo NK Cell Priming

Park,

Kim,

Jangid

et al. 2024

IJMS

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Current cytokine-based natural killer (NK) cell priming techniques have exhibited limitations such as the deactivation of biological signaling molecules and subsequent insufficient maturation of the cell population during mass cultivation processes. In this study, we developed an amphiphilic trigonal 1,2-distearoyl-sn-glycero-3-phosphorylethanolamine (DSPE) lipid-polyethylene glycol (PEG) material to assemble NK cell clusters via multiple hydrophobic lipid insertions into cellular membranes. Our lipid conjugate-mediated ex vivo NK cell priming sufficiently augmented the structural modulation of clusters, facilitated diffusional signal exchanges, and finally activated NK cell population with the clusters. Without any inhibition in diffusional signal exchanges and intrinsic proliferative efficacy of NK cells, effectively prime NK cell clusters produced increased interferon-gamma, especially in the early culture periods. In conclusion, the present study demonstrates that our novel lipid conjugates could serve as a promising alternative for future NK cell mass production.

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Enhanced Calcium Signal Induces NK Cell Degranulation but Inhibits Its Cytotoxic Activity

Abstract: The raw files presented in this article have been submitted to the Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi) under accession number GSE184127.

Cited by 6 publications

References 38 publications

Differential effects on natural killer cell production by membrane‐bound cytokine stimulations

Differential effects on natural killer cell production by membrane‐bound cytokine stimulations

pHLIP-fused PD-L1 engages avelumab to elicit NK cytotoxicity under acidic conditions

Networked Cluster Formation via Trigonal Lipid Modules for Augmented Ex Vivo NK Cell Priming

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