Biology subjects

Vivier, E.

Publications and source records attributed to Vivier, E..

5 recordsLinked to original sources

bioRxiv2025

Natural killer cell TGF- signaling regulates senolytic activity and vascular patterning in the postnatal lung

BackgroundBronchopulmonary dysplasia (BPD) is a disease of neonatal lung development that is linked to impaired pulmonary vascularization, dysregulated transforming growth factor-{beta} (TGF-{beta}) signaling and the accumulation of senescent cells. Despite the established role for TGF-{beta} signaling in promoting vascular remodeling and suppressing the senolytic activity of natural killer (NK) cells, the contribution of NK cell TGF-{beta} signaling to postnatal lung patterning and the pathogenesis of BPD remains unclear. MethodsMice bearing an NK cell-selective deletion of the type-II TGF-{beta} receptor (Tgfbr2NK-/-) were analyzed for vascular and alveolar structure, lung NK cell infiltration, senescence markers and lung function testing across neonatal and adult timepoints. Single-cell RNA sequencing of lung tissue from both neonatal mice and human infants with BPD was performed. The effect of enhanced NK cell activity in a hyperoxia-induced model of BPD was assessed in Tgfbr2NK-/-neonates, as well as pharmacologically, using the TGF-{beta} ligand trap/IL-15 superagonist, HCW9218. ResultsNeonatal Tgfbr2NK-/- mice exhibited a baseline reduction in distal arteriolar density, impaired alveolarization, and sex-specific deficits in long-term lung function. Single-cell RNA sequencing identified the excessive clearance of senescent endothelial cells by TGF-{beta} insensitive NK cells in the lungs of Tgfbr2NK-/- neonates, which served as a contributor of the BPD-like phenotype observed in naive animals. Tgfbr2NK-/- mice were protected from impaired lung development in the hyperoxia model. Sequencing from lung tissue from infants with BPD confirmed excessive TGF-{beta} signaling and cytotoxic impairment in NK cells. Treatment with HCW9218 prevented senescent cell accumulation and rescued lung development in the hyperoxia mouse model. ConclusionsThese findings identify TGF-{beta} as a tunable regulator of NK cell senolytic activity that is essential to normal postnatal lung development. Excessive NK cell TGF-{beta} signaling contributes to impaired lung development following exposure to neonatal hyperoxia and may serve as a viable therapeutic target for human BPD.

developmental biology↗

bioRxiv2025

Integrated single cell analysis identifies CD39+ tumor-associated NK cells with cytotoxic potential in lung cancer

Natural killer (NK) cell-targeting immunotherapies are emerging, yet the differentiation and functional states of tumor-infiltrating NK cells remain poorly understood. Using matched single-nucleus RNA and ATAC sequencing of non-small cell lung cancer (NSCLC) specimens, we resolved the transcriptional and epigenetic landscape of intratumoral NK cells. We identified two tumor-associated NK (taNK) cell subsets marked by ITGAE (CD103) and ITGA1 (CD49a) that display features of tissue residency and dysfunction while preserving cytotoxic function. Trajectory and regulon analyses revealed an inflammation-driven transition from early GZMK NKs toward an ENTPD1+ (CD39) effector state characterized by interferon-stimulated gene (ISG) programs. Functional profiling established CD39 taNK as the dominant cytotoxic NK cell population with superior killing capacity that is further potentiated by NKG2A blockade. This study offers mechanistic insights into NK cell differentiation in NSCLC and establishes CD39 taNK cells as a targetable effector population for immunotherapy. One sentence summaryMultiomic analysis identifies CD39+ tumor-associated NK cells as a cytotoxic effector state in NSCLC responsive to NKG2A blockade.

immunology↗

bioRxiv2024

Genome-wide CRISPR/Cas9 screen reveals factors that influence the susceptibility of tumor cells to NK cell-mediated killing

BackgroundNatural killer (NK) cells exhibit potent cytotoxic activity against various cancer cell types. Over the past five decades, numerous methodologies have been employed to elucidate the intricate molecular mechanisms underlying NK cell-mediated tumor control. While significant progress has been made in elucidating the interactions between NK cells and tumor cells, the regulatory factors governing NK cell-mediated tumor cell destruction are not yet fully understood. This includes the diverse array of tumor ligands recognized by NK cells and the mechanisms that NK cells employ to eliminate tumor cells. MethodsIn this study, we employed a genome-wide CRISPR/Cas9 screening approach in conjunction with functional cytotoxicity assays to delineate the proteins modulating the susceptibility of colon adenocarcinoma HCT-116 cells to NK cell-mediated cytotoxicity. ResultsAnalysis of guide RNA (gRNA) distribution in HCT-116 cells that survived co-incubation with NK cells identified ICAM-1 as a pivotal player in the NKp44-mediated immune synapse, with NKp44 serving as an activating receptor crucial for the elimination of HCT-116 tumor cells by NK cells. Furthermore, disruption of genes involved in the apoptosis or IFN-{gamma} signaling pathways conferred resistance to NK cell attack. We further dissected that NK cell-derived IFN-{gamma} promotes mitochondrial apoptosis in vitro and exerts control over B16-F10 lung metastases in vivo. ConclusionMonitoring ICAM-1 levels on the surface of tumor cells or modulating its expression should be considered in the context of NK cell-based therapy. Additionally, considering the diffusion properties of IFN-{gamma}, our findings highlight the potential of leveraging NK cell-derived IFN-{gamma} to enhance direct tumor cell killing and facilitate bystander effects via cytokine diffusion, warranting further investigation. WHAT IS ALREADY KNOWN ON THIS TOPICNK cells play a crucial role in identifying and eliminating various cancer cell types. However, the mechanisms that regulate NK cell-mediated destruction of tumor cells are not yet fully understood. This involves the array of tumor ligands that NK cells recognize and the processes they utilize to carry out tumor cell elimination. WHAT THIS STUDY ADDSOur research emphasizes the critical role of ICAM-1 in NKp44-mediated destruction of HCT-116 tumor cells. Additionally, we found that interfering with genes related to apoptosis or IFN-{gamma} signaling pathways increased resistance to NK cell attack. We showed that IFN-{gamma} produced by NK cells induces mitochondrial apoptosis in vitro and helps regulate B16-F10 lung metastases in vivo. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICYGiven the ability of IFN-{gamma} to diffuse, our findings suggest that NK cell-derived IFN-{gamma} can be harnessed to directly kill tumor cells and trigger bystander effects through cytokine spread. This approach holds promise for further exploration. Additionally, assessing or manipulating ICAM-1 levels on tumor cell surfaces could enhance the effectiveness of NK cell-based therapies.

immunology↗

bioRxiv2021

CISH targeting in NK cells activates natural cytotoxicity receptor signaling and reduce cell exhaustion to unsilence primary anti-tumor response

Cytokine inducible SH2-containing protein (CISH) is a natural killer (NK) cell negative regulator of cytokine signaling pathway. To further understand CISH functions in NK cells, we developed a conditional Cish-deficient mouse model in NK cells (Cishfl/flNcr1Ki/+). We detected no developmental or homeostatic difference in NK cells. However, global gene expression of Cishfl/flNcr1Ki/+ NK cells compared to Cish+/+Ncr1Ki/+ NK cells revealed upregulation of pathways and genes associated with NK cell cycling and activation. We show that CISH does not only regulate interleukin-15 (IL-15) signaling pathways but also natural cytotoxicity receptors (NCR) pathways. Indeed, CISH protein expression level increases upon NCR triggering. Primed Cishfl/flNcr1Ki/+ NK cells display increased activation upon NCR stimulation. Cishfl/flNcr1Ki/+ NK cells display lower activation thresholds and Cishfl/flNcr1Ki/+ mice are more resistant to tumor metastasis. Remarkably, we found that Cishfl/flNcr1Ki/+ mice were also more resistant to primary breast cancer growth in addition to superior control of spontaneous tumor metastasis. CISH deletion favors NK cell accumulation to the primary tumor, optimizes NK cell killing properties and decreases TIGIT immune checkpoint receptor expression, limiting NK cell exhaustion. Finally, we argue that specifically enhancing NK cell function is sufficient to boost anti-tumor response to both primary and secondary tumor models. Using CRISPRi, we then targeted CISH in human NK-92 or primary NK cells. According to the results in our mouse model, CISH deletion favors NCR signaling and anti-tumor functions in human NK cells. Our results validate CISH as an emerging therapeutic target to enhance NK cell immunotherapy.

immunology↗

bioRxiv2018

Therapeutic blockade of Activin-A improves NK cell function and anti-tumor immunity

Natural killer (NK) cells are innate lymphocytes that play a major role in immunosurveillance against tumor initiation and metastasis spread. Signals and checkpoints that regulate NK cell fitness and function in the tumor microenvironment are not well defined. Transforming grow factor (TGF)-{beta} is a recognized suppressor of NK cells that inhibits IL-15 dependent signaling events and induces cellular transdifferentiation, however the role of other SMAD signaling pathways in NK cells is unknown. In this report, we show that NK cells express the type I Activin receptor, ALK4, which upon binding its ligand Activin-A, phosphorylates SMAD2/3 to efficiently suppress IL-15-mediated NK cell metabolism. Activin-A impairs human and mouse NK cell proliferation and downregulates intracellular granzyme B levels to impair tumor killing. Similar to TGF-{beta}, Activin-A also induced SMAD2/3 phosphorylation and drove NK cells to upregulate several ILC1-like surface markers including CD69, TRAIL and CD49a. Activin-A also induced these changes on TGF-{beta} receptor deficient NK cells, highlighting that Activin-A and TGF-{beta} are independent pathways that drive SMAD2/3-mediated NK cell suppression. Finally, therapeutic inhibition of Activin-A by Follistatin significantly slowed orthotopic melanoma growth in mice. These data highlight independent SMAD2/3 pathways target NK cell fitness and function and identify a novel therapeutic axis to promote tumor immunity.\n\nOne Sentence Summary: Activin-A can directly inhibit NK cell effector functions, promote NK cells transdifferentiation into ILC1-like cells and suppress anti-melanoma immunity.

immunology↗