Memory-like natural killer cells facilitate effector functions of daratumumab in multiple myeloma
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ABSTRACT:
PROVIDER: PRJNA658903 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12506861.fastq.gz | Fastqsanger.gz | |||
| SRR12506862.fastq.gz | Fastqsanger.gz | |||
| SRR12506863.fastq.gz | Fastqsanger.gz |
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Project description:Natural killer (NK) cells support the anti-myeloma activity of daratumumab via antibody-dependent cellular cytotoxicity (ADCC) in multiple myeloma (MM). However, the different roles of heterogeneous NK cell subpopulations have not been elucidated in MM. Here, we delineate memory-like NK cells in the bone marrow (BM) of newly diagnosed MM (NDMM) patients using single-cell RNA sequencing, and further characterize their distinct immunophenotypic features and functions by multicolor flow cytometry. Memory-like NK cells exert robust daratumumab-mediated effector functions ex vivo, including cytokine production and degranulation, compared to conventional NK cells. The composition of memory-like NK cells in BM determines the daratumumab-mediated ex vivo functional activity of BM NK cells in NDMM patients. Unlike conventional NK cells, sorted memory-like NK cells from the BM of NDMM patients exert substantial cytotoxic activity against myeloma cells in the presence of daratumumab. Our findings indicate that memory-like NK cells are an important mediator of daratumumab-dependent effector functions in MM and support direct future efforts to better predict and improve the clinical efficacy of therapeutic antibodies by selectively employing memory-like NK cells.
2021-08-01 | GSE155795 | GEO
Project description:Natural Killer cells (NK), a major constituent of innate immune system, have the ability to kill the transformed and infected cells without prior sensitization; can be put to immunotherapeutic use against various malignancies. NK cells discriminate between normal cells and transformed cells via a balance of inhibitory and activating signals induced by interactions between NK cell receptors and target cell ligands. Present study investigates whether expansion of NK cells could augment their anti-myeloma (MM) activity. For NK cell expansion, peripheral blood mononuclear cells from healthy donors and myeloma patients were co-cultured with irradiated K562 cells transfected with 4-1BBL and membrane-bound IL15 (K562-mb15-41BBL). A genome-wide profiling approach was performed to identify gene expression signature in expanded NK (ENK) cells and non-expanded NK cells isolated from healthy donors and myeloma patients. A specific set of genes involved in proliferation, migration, adhesion, cytotoxicity, and activation were up regulated post expansion, also confirmed by flow cytometry. Exp-NK cells killed both allogeneic and autologous primary MM cells more avidly than non-exp-NK cells in vitro. Multiple receptors, particularly NKG2D, natural cytotoxicity receptors, and DNAM-1 contributed to target lysis, via a perforin mediated mechanism. In summary, vigorous expansion and high anti-MM activity both in vitro and in vivo provide the rationale for testing exp-NK cells in a clinical trial for high risk MM. Differential gene expression profile in expanded natural killer (ENK) cells and non-expanded natural killer (NK) cells from healthy donors and myeloma patients Eight healthy donor and eight myeloma patients were used in the study. Non-expanded natural killer (NK) cells were isolated from PBMCs of healthy donors and myeloma patients. Expanded natural killer (ENK) cells were generated from same set of samples as mentioned in expansion protocol. All ENK and NK cells were used for gene expression profiling.
2011-03-08 | E-GEOD-27838 | biostudies-arrayexpress
Project description:Natural Killer cells (NK), a major constituent of innate immune system, have the ability to kill the transformed and infected cells without prior sensitization; can be put to immunotherapeutic use against various malignancies. NK cells discriminate between normal cells and transformed cells via a balance of inhibitory and activating signals induced by interactions between NK cell receptors and target cell ligands. Present study investigates whether expansion of NK cells could augment their anti-myeloma (MM) activity. For NK cell expansion, peripheral blood mononuclear cells from healthy donors and myeloma patients were co-cultured with irradiated K562 cells transfected with 4-1BBL and membrane-bound IL15 (K562-mb15-41BBL). A genome-wide profiling approach was performed to identify gene expression signature in expanded NK (ENK) cells and non-expanded NK cells isolated from healthy donors and myeloma patients. A specific set of genes involved in proliferation, migration, adhesion, cytotoxicity, and activation were up regulated post expansion, also confirmed by flow cytometry. Exp-NK cells killed both allogeneic and autologous primary MM cells more avidly than non-exp-NK cells in vitro. Multiple receptors, particularly NKG2D, natural cytotoxicity receptors, and DNAM-1 contributed to target lysis, via a perforin mediated mechanism. In summary, vigorous expansion and high anti-MM activity both in vitro and in vivo provide the rationale for testing exp-NK cells in a clinical trial for high risk MM. Differential gene expression profile in expanded natural killer (ENK) cells and non-expanded natural killer (NK) cells from healthy donors and myeloma patients
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Project description:Bach2 negatively regulates natural killer cell maturation and effector program
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Project description:CD38 is a surface ectoenzyme expressed at high levels on myeloma plasma cells and is the target for the monoclonal antibodies (mAbs) daratumumab and isatuximab. CD38 density on tumor cells is an important determinant of mAb efficacy while CD38 is lost after mAb treatment. Several small molecules have been found to increase tumor surface CD38, with the goal of boosting mAb efficacy in a co-treatment strategy. Here we sought to extend our currently limited insight into CD38 surface expression by using a multi-omics approach. Genome-wide CRISPR-interference screens integrated with patient-centered epigenetic analysis confirmed known regulators of CD38, such as RARA, while revealing XBP1 and SPI1 as other key transcription factors governing surface CD38 levels. CD38 knockdown followed by cell surface proteomics demonstrated no significant remodeling of the myeloma “surfaceome” after genetically-induced loss of this antigen. Integrated transcriptome and surface proteome data confirmed high specificity of all-trans retinoic acid in upregulating CD38 in contrast to broader effects of azacytidine and panobinostat. Finally, unbiased phosphoproteomics identified inhibition of MAP kinase pathway signaling in tumor cells after daratumumab treatment. Our work provides a resource to design strategies to enhance efficacy of CD38-targeting immunotherapies in myeloma.
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Project description:Comparing global gene expression of neonatal and adult natural killer cells to determine if differences in gene expression suggest that different developmental pathways during hematopoiesis are followed in the fetal and adult mouse to produce mature natural killer cells.
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Project description:Natural killer (NK) cells are innate lymphocytes important for early host defense against infectious pathogens and surveillance against malignant transformation. Resting murine NK cells regulate the translation of effector molecule mRNAs (e.g. granzyme B, GzmB) through unclear molecular mechanisms. MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate the translation of their mRNA targets, and are therefore candidates mediating this control process. While the expression and importance of miRNAs in T and B lymphocytes has been established, little is known about miRNAs in NK cells. Here, we utilized two next-generation sequencing (NGS) platforms to define the miRNA transcriptomes of resting and cytokine-activated primary murine NK cells, with confirmation by RT-qPCR and microarrays. We delineate a bioinformatics analysis pipeline that identified 302 known and 28 novel mature miRNAs from sequences obtained from NK cell small RNA libraries. These miRNAs are expressed over a broad range, exhibit isomiR complexity, and a subset is differentially expressed following cytokine-activation. Using this miRNA NGS data, miR-223 was identified as a mature miRNA present in resting NK cells with decreased expression following cytokine-activation. Further, we demonstrate that miR-223 specifically targets the 3’UTR of murine GzmB in vitro, indicating that this miRNA may contribute to control of GzmB translation in resting NK cells. Thus, the sequenced NK cell miRNA transcriptome provides a valuable framework for further elucidation of miRNA expression and function in NK cell biology. Illumina GA (SRR036363, SRR036364) and SOLiD (SRR036206, SRR036210) sequencing data have been submitted to the NCBI Sequence Read Archive (SRA). The study uses a custome made array to characterize miRNA of activated and resting murine splenic natural killer cells
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Project description:Bach2 has been reported to regulate multiple immune cell development and function. Here we report that Bach2 is constitutively expressed in relatively immature NK subsets. Bach2 negatively regulates NK cell development and Bach2 deficiency results in NK cell with mature effector phenotype. Thus, Bach2 functions as a negative regulator of NK cell maturation and function.
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