Myeloma cells induce the accumulation of activated CD94low NK cells by cell-to-cell contacts involving CD56 molecules

Barberi, Chiara; Pasquale, Claudia De; Allegra, Alessandro; Migliore, Giacomo Sidoti; Oliveri, Daniela; Loiacono, Fabrizio; Innao, Vanessa; Musolino, Caterina; Pende, Daniela; Cantoni, Claudia; Carrega, Paolo; Mingari, Maria Cristina; Campana, Stefania; Ferlazzo, Guido

doi:10.1182/bloodadvances.2019000953

Cited by 14 publications

(16 citation statements)

References 32 publications

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“…A recent study using single-cell RNA sequencing showed enrichment of NK cell populations during MGUS, and phenotypic shifts later in MM progression that potentially point to a compromised immune system ( 66 ). Discrepancy is also observed in terms of NK cell functionality where either reduced NK cell function ( 65 ) or high NK cell function ( 59 , 67 ) are linked with advanced clinical stage, high-risk disease and reduced survival.…”

Section: Nk Cell Surveillance Of Malignant Cellsmentioning

confidence: 99%

“…Due to the complexity, heterogeneity, and plasticity of NK cells in cancer patients, the discrepancies are difficult to distill into a single explanation ( 67 ). One likely explanation seems to relate back to which NK cell subpopulations are being measured.…”

Section: Nk Cell Surveillance Of Malignant Cellsmentioning

confidence: 99%

“…This reduction in MICA/B levels on the myeloma cells leads to loss of NK cell activation through NKG2D receptor, allowing MM cells to evade NK cell surveillance ( 69 , 70 ). Alternatively, HLA-I ligand upregulation on MM cells may also block NK cell activity ( 67 , 71 ). Interestingly, myeloma cells harvested from MM patients from the BM early in disease progression expressed a relatively low level of HLA Class I ligands and were subsequently responsive to the NK cell mediated cytotoxicity.…”

Section: Nk Cell Surveillance Of Malignant Cellsmentioning

confidence: 99%

“…Although there is limited knowledge regarding the role of NKG2A in MM, in-vitro experiments showed that the level of HLA-E on the myeloma cells could potentiate the inhibition of NKG2A ( 67 ). This suggests that anti-NKG2A may be beneficial for patients that have functional levels of HLA-E ( 67 , 148 ), although studies proving this hypothesis are still ongoing. This preliminary evidence, combined with positive preclinical studies in other malignancies ( 149 , 156 ), points to the therapeutic potential of blocking NKG2A in MM.…”

Section: Nk Cell Irsmentioning

confidence: 99%

“…Previous trials proposed that the intra-tumoral level of IRs such as PD-1 on TILs were significant determinants of success for IR mAb therapies ( 242 ). However, there is not only heterogeneity in the percentage and activity of NK cells within a MM patient population ( 59 , 65 , 67 ), but also in the expression of specific IRs or ligands. Such differential expression can affect activity of NK cell functionality.…”

Section: Perspectivesmentioning

confidence: 99%

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Targeting NK Cell Inhibitory Receptors for Precision Multiple Myeloma Immunotherapy

et al. 2020

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Innate immune surveillance of cancer involves multiple types of immune cells including the innate lymphoid cells (ILCs). Natural killer (NK) cells are considered the most active ILC subset for tumor elimination because of their ability to target infected and malignant cells without prior sensitization. NK cells are equipped with an array of activating and inhibitory receptors (IRs); hence NK cell activity is controlled by balanced signals between the activating and IRs. Multiple myeloma (MM) is a hematological malignancy that is known for its altered immune landscape. Despite improvements in therapeutic options for MM, this disease remains incurable. An emerging trend to improve clinical outcomes in MM involves harnessing the inherent ability of NK cells to kill malignant cells by recruiting NK cells and enhancing their cytotoxicity toward the malignant MM cells. Following the clinical success of blocking T cell IRs in multiple cancers, targeting NK cell IRs is drawing increasing attention. Relevant NK cell IRs that are attractive candidates for checkpoint blockades include KIRs, NKG2A, LAG-3, TIGIT, PD-1, and TIM-3 receptors. Investigating these NK cell IRs as pathogenic agents and therapeutic targets could lead to promising applications in MM therapy. This review describes the critical role of enhancing NK cell activity in MM and discusses the potential of blocking NK cell IRs as a future MM therapy.

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Section: Nk Cell Surveillance Of Malignant Cellsmentioning

confidence: 99%

Section: Nk Cell Surveillance Of Malignant Cellsmentioning

confidence: 99%

Section: Nk Cell Surveillance Of Malignant Cellsmentioning

confidence: 99%

Section: Nk Cell Irsmentioning

confidence: 99%

Section: Perspectivesmentioning

confidence: 99%

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Targeting NK Cell Inhibitory Receptors for Precision Multiple Myeloma Immunotherapy

et al. 2020

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Single‐cell transcriptome profiling reveals the key role of ZNF683 in natural killer cell exhaustion in multiple myeloma

Chen

Wan

et al. 2022

Clinical & Translational Med

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Backgrounds Decreased cytotoxicity of natural killer (NK) cells has been shown in multiple myeloma (MM). However, the underlying molecular mechanisms remain unclear. Here, by using single‐cell RNA sequencing analysis and in vitro experiments, we aim to uncover and validate molecularly distinctive insights into identifying regulators for NK cell exhaustion and provide potential targets for novel immune therapies in MM. Methods Single‐cell RNA sequencing was conducted in the bone marrow and peripheral blood samples from 10 newly diagnosed MM patients and three healthy volunteers. Based on the cluster‐defining differentially expressed genes, we named and estimated functional states of each cluster via bioinformatics analyses. Functional significance of key findings obtained from sequencing analysis was examined in a series of in vitro experiments, including luciferase reporter assay, lentiviral expression vector construction, NK cell transfection, RT‐qPCR, flow cytometry, and cytotoxicity assay. Results We classified NK cells into seven distinct clusters and confirmed that a subset of ZNF683 + NK cells were enriched in MM patients with ‘exhausted’ transcriptomic profile, featuring as decreased expression of activating receptors and cytolytic molecules, as well as increased expression of inhibitory receptors. Next, we found a significant downregulation of SH2D1B gene that encodes EAT‐2, an adaptor protein of activating receptor SLAMF7, in ZNF683 + NK cells from MM patients versus healthy volunteers. We further proved that ZNF683 transfection in NK cells significantly downregulated SH2D1B expression via directly binding to the promoter of SH2D1B , leading to NK cell cytotoxic activity impairment and exhausted phenotypes acquisition. In contrast, ZNF683 knockout in NK cells from MM patients increased cytotoxic activity and reversed NK cell exhaustion. Conclusions In summary, our findings uncover an important mechanism of ZNF683 + NK cell exhaustion and suggest that transcriptional suppressor ZNF683 as a potential useful therapeutic target in immunotherapy of MM.

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Exploring natural killer cell-related biomarkers in multiple myeloma: a novel nature killer cell-related model predicting prognosis and immunotherapy response using single-cell study

Zhao,

Wang,

Zhu

et al. 2024

Clin Exp Med

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Background Natural killer cells (NKs) may be involved in multiple myeloma (MM) progression. The present study elucidated the correlation between NKs and the progression of MM using single-cell binding transcriptome probes to identify NK cell-related biomarkers. Methods Single-cell analysis was performed including cell and subtype annotation, cell communication, and pseudotime analysis. Hallmark pathway enrichment analysis of NKs and NKs-related differentially expressed genes (DEGs) were conducted using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein–protein interaction (PPI) networks. Then, a risk model was structured based on biomarkers identified through univariate Cox regression analysis and least absolute shrinkage and selection operator regression analysis and subsequently validated. Additionally, correlation of clinical characteristics, gene set enrichment analysis, immune analysis, regulatory network, and drug forecasting were explored. Results A total of 13 cell clusters were obtained and annotated, including 8 cell populations that consisted of NKs. Utilizing 123 PPI network node genes, 8 NK-related DEGs were selected to construct a prognostic model. Immune cell infiltration results suggested that 11 immune cells exhibited marked differences in the high and low-risk groups. Finally, the model was used to screen potential drug targets to enhance immunotherapy efficacy. Conclusion A new prognostic model for MM associated with NKs was constructed and validated. This model provides a fresh perspective for predicting patient outcomes, immunotherapeutic response, and candidate drugs.

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Myeloma cells induce the accumulation of activated CD94low NK cells by cell-to-cell contacts involving CD56 molecules

Cited by 14 publications

References 32 publications

Targeting NK Cell Inhibitory Receptors for Precision Multiple Myeloma Immunotherapy

Targeting NK Cell Inhibitory Receptors for Precision Multiple Myeloma Immunotherapy

Single‐cell transcriptome profiling reveals the key role of ZNF683 in natural killer cell exhaustion in multiple myeloma

Exploring natural killer cell-related biomarkers in multiple myeloma: a novel nature killer cell-related model predicting prognosis and immunotherapy response using single-cell study

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