Perturbed NK-cell homeostasis associated with disease severity in chronic neutropenia

Sohlberg, Ebba; Pfefferle, Aline; Ask, Eivind Heggernes; Tschan-Plessl, Astrid; Jacobs, Bénédikt; Netskar, Herman; Lorenz, Susanne; Kanaya, Minoru; Kosugi-Kanaya, Mizuha; Meinke, Stephan; Mörtberg, Anette; Höglund, Petter; Sundin, Mikael; Carlsson, Göran; Palmblad, Jan; Malmberg, Karl‐Johan

doi:10.1182/blood.2021013233

Cited by 11 publications

(12 citation statements)

References 58 publications

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“…In mice lacking neutrophils due to mutations in Gfi-1 , NK cells hyperproliferate, yet they have poor survival, impaired function, and a block in maturation ( 52 ). Furthermore, some individuals with congenital neutropenia have a decreased frequency of CD56 dim NK cells in the periphery and NK cell functional impairment ( 52 , 53 ), a phenotype very similar to that seen in MCM- and GINS-deficient individuals. In the proband (II.1) described in our study, as in GINS1 deficiency, neutropenia was corrected by treatment with G-CSF.…”

Section: Discussionmentioning

confidence: 89%

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Partial loss-of-function mutations in GINS4 lead to NK cell deficiency with neutropenia

Conte¹,

Poli²,

Taglialatela³

et al. 2022

JCI Insight

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Human NK cell deficiency (NKD) is a primary immunodeficiency in which the main clinically relevant immunological defect involves missing or dysfunctional NK cells. Here, we describe a familial NKD case in which 2 siblings had a substantive NKD and neutropenia in the absence of other immune system abnormalities. Exome sequencing identified compound heterozygous variants in Go-Ichi-Ni-San (GINS) complex subunit 4 ( GINS4 , also known as SLD5 ), an essential component of the human replicative helicase, which we demonstrate to have a damaging impact upon the expression and assembly of the GINS complex. Cells derived from affected individuals and a GINS4 -knockdown cell line demonstrate delayed cell cycle progression, without signs of improper DNA synthesis or increased replication stress. By modeling partial GINS4 depletion in differentiating NK cells in vitro, we demonstrate the causal relationship between the genotype and the NK cell phenotype, as well as a cell-intrinsic defect in NK cell development. Thus, biallelic partial loss-of-function mutations in GINS4 define a potentially novel disease-causing gene underlying NKD with neutropenia. Together with the previously described mutations in other helicase genes causing NKD, and with the mild defects observed in other human cells, these variants underscore the importance of this pathway in NK cell biology.

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Section: Discussionmentioning

confidence: 89%

“…In other words, perhaps the neutrophil deficiency is extrinsic and secondary to the deficiency of NK cells. Alternatively, there may be a unique requirement associated with immune cell proliferation and apoptosis that is common to NK cells and neutrophils ( 53 ).…”

Section: Discussionmentioning

confidence: 99%

Partial loss-of-function mutations in GINS4 lead to NK cell deficiency with neutropenia

Conte¹,

Poli²,

Taglialatela³

et al. 2022

JCI Insight

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“…In NK cells, 54 upregulated and 7 downregulated genes were identified in HCC, most of which had been reported to be involved in the p53 signaling pathway and cell cycles, such as CCNB1, CCNB2, CDK1, PTTG1, PLK1, MAD2L1, GTSE1, and TOP2A. These genes and related pathways were demonstrated to maintain NK cell homeostasis ( 24 ). Moreover, some other DEGs, including HSPA1A, HSPA1B, HSPA5, HSPA6, IFNG, CD8B, and KIR2DL3, were reported to participate in antigen processing and presentation.…”

Section: Resultsmentioning

confidence: 99%

Single-Cell Transcriptomic Analysis Reveals Macrophage–Tumor Crosstalk in Hepatocellular Carcinoma

Liu

Zhang

Ju³

et al. 2022

Front. Immunol.

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As one of the most malignant cancer, hepatocellular carcinoma (HCC) has a complex ecosystem featured by high heterogeneity. Cell crosstalk is demonstrated to be critical for HCC development. However, the cell communication orchestration in HCC remains largely unknown. Here, by analyzing the single-cell transcriptomes of the primary tumor tissues (n = 10) and tumor-adjacent tissues (n = 8) derived from 10 patients with HCC, we found that the proportions of plasmacytoid dendritic cells (pDCs) and natural killer (NK) cells were reduced and that the proportion of macrophages was increased in the immune component of the primary tumor, compared with those in the tumor-adjacent tissue. Furthermore, we found widespread communication between macrophage populations and other cell types, and this communication was remarkably strengthened in the primary tumor, especially with HCC malignant cells. In addition, the SPP1–CD44 axis was identified as a unique interaction between macrophages and HCC malignant cells. Our comprehensive portrait of cell communication patterns over the HCC ecosystem reveals further insights into immune infiltration.

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“…Nevertheless, according to our results, the allogeneic NK-mediated GVL effects were transient after engraftment in the murine MHC class I mismatched HSCT setting. Recently, the effect of NK regulated by neutrophils in human has been reported which found that patients with chronic neutropenia displayed a specific gap in the NK repertoire, associated with poor cytotoxic function and more severe disease manifestations [ 36 ]. The GVL effects of NK cells were transient due to a problem at the functional maturation of NK cell after HSCT; thus, appropriate stimulation for NK cell licensing by enriched neutrophils should be needed.…”

Section: Discussionmentioning

confidence: 99%

Improved Antitumor Effect of NK Cells Activated by Neutrophils in a Bone Marrow Transplant Model

Nakato

Iwamoto

Amano

et al. 2023

Mediators of Inflammation

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The licensing process mediated by inhibitory receptors of the Ly49 C-type lectin superfamily that recognizes self-major histocompatibility complex (MHC) class I in mice is essential for the proper antitumor function of natural killer (NK) cells. Several models for NK cell licensing can be exploited for adoptive immunotherapy for cancer. However, the appropriate adoptive transfer setting to induce efficient graft versus tumor/leukemia effects remains elusive, especially after hematopoietic stem cell transplantation (HSCT). In our previous experiment, we showed that intraperitoneal neutrophil administration with their corresponding NK receptor ligand-activated NK cells using congenic mice without HSCT. In this experiment, we demonstrate enhanced antitumor effects of licensed NK cells induced by weekly intraperitoneal injections of irradiated neutrophil-enriched peripheral blood mononuclear cells (PBMNCs) in recipient mice bearing lymphoma. Bone marrow transplantation was performed using BALB/c mice (H-2d) as the recipient and B10 mice (H-2b) as the donor. The tumor was A20, a BALB/c-derived lymphoma cell line, which was injected subcutaneously into the recipient at the same time as the HSCT. Acute graft versus host disease was not exacerbated in this murine MHC class I mismatched HSCT setting. The intraperitoneal injection of PBMNCs activated a transient licensing of NK subsets expressed Ly49G2, its corresponding NK receptor ligand to H-2d, and reduced A20 tumor growth in the recipient after HSCT. Pathological examination revealed that increased donor-oriented NK1.1+NK cells migrated into the recipient tumors, depending on neutrophil counts in the administered PBMNCs. Collectively, our data reveal a pivotal role of neutrophils in promoting NK cell effector functions and adoptive immunotherapy for cancer.

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Perturbed NK-cell homeostasis associated with disease severity in chronic neutropenia

Cited by 11 publications

References 58 publications

Partial loss-of-function mutations in GINS4 lead to NK cell deficiency with neutropenia

Partial loss-of-function mutations in GINS4 lead to NK cell deficiency with neutropenia

Single-Cell Transcriptomic Analysis Reveals Macrophage–Tumor Crosstalk in Hepatocellular Carcinoma

Improved Antitumor Effect of NK Cells Activated by Neutrophils in a Bone Marrow Transplant Model

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