Dataset Information

Combined analysis of bulk and single-cell RNA sequencing reveals novel natural killer cell-related prognostic biomarkers for predicting immunotherapeutic response in hepatocellular carcinoma.

ABSTRACT:

Introduction

Natural killer (NK) cells play an irreplaceable and important role as a subtype of innate immune cells in the contemporary setting of antitumor immunity.

Methods

We chose a total of 1,196 samples for this analysis from the public dataset's six separate cohorts. To identify 42 NK cell marker genes, we first carried out a thorough study of single-cell RNA sequencing data from the GSE149614 cohort of hepatocellular carcinoma (HCC).

Results

Using the NK cell marker genes in the TCGA cohort, we next created a seven-gene prognostic signature, separating the patients into two categories with distinct survival patterns. This signature's prognostic prediction ability was well verified across several validation cohorts. Patients with high scores had higher TIDE scores but lower immune cell infiltration percentages. Importantly, low-scoring patients had superior immunotherapy response and prognosis than high-scoring patients in an independent immunotherapy cohort (IMvigor210). Finally, we used CD56 and TUBA1B antibodies for immunohistochemical labeling of HCC tissue sections, and we discovered a lower number of CD56+ cells in the HCC tissue sections with high TUBA1B expression.

Discussion

In summary, our research created a unique prognostic profile based on NK cell marker genes that may accurately predict how well immunotherapy would work for HCC patients.

SUBMITTER: Zhang K

PROVIDER: S-EPMC10086229 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Combined analysis of bulk and single-cell RNA sequencing reveals novel natural killer cell-related prognostic biomarkers for predicting immunotherapeutic response in hepatocellular carcinoma.

Zhang Kai K Yuan Enwu E

Frontiers in immunology 20230328

<h4>Introduction</h4>Natural killer (NK) cells play an irreplaceable and important role as a subtype of innate immune cells in the contemporary setting of antitumor immunity.<h4>Methods</h4>We chose a total of 1,196 samples for this analysis from the public dataset's six separate cohorts. To identify 42 NK cell marker genes, we first carried out a thorough study of single-cell RNA sequencing data from the GSE149614 cohort of hepatocellular carcinoma (HCC).<h4>Results</h4>Using the NK cell marker ...[more]

PMID: 37056756

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Project description:BackgroundCombination antiretroviral therapy (cART) has dramatically extended the life expectancy of people living with HIV-1 and improved their quality of life. There is nevertheless no cure for HIV-1 infection since HIV-1 persists in viral reservoirs of latently infected CD4+ T cells. cART does not eradicate HIV-1 reservoirs or restore cytotoxic natural killer (NK) cells which are dramatically reduced by HIV-1 infection, and express the checkpoint inhibitors NKG2A or KIR2DL upregulated after HIV-1 infection. Cytotoxic NK cells expressing the homing receptor CXCR5 were recently described as key subsets controlling viral replication.MethodsWe designed and evaluated the potency of "Natural killer activating Multimeric immunotherapeutic compleXes", called as NaMiX, combining multimers of the IL-15/IL-15Rα complex with an anti-NKG2A or an anti-KIR single-chain fragment variable (scFv) to kill HIV-1 infected CD4+ T cells. The oligomerization domain of the C4 binding protein was used to associate the IL-15/IL-15Rα complex to the scFv of each checkpoint inhibitor as well as to multimerize each entity into a heptamer (α form) or a dimer (β form). Each α or β form was compared in different in vitro models using one-way ANOVA and post-hoc Tukey's tests before evaluation in humanized NSG tg-huIL-15 mice having functional NK cells.ResultsAll NaMiX significantly enhanced the cytolytic activity of NK and CD8+ T cells against Raji tumour cells and HIV-1+ ACH-2 cells by increasing degranulation, release of granzyme B, perforin and IFN-γ. Targeting NKG2A had a stronger effect than targeting KIR2DL due to higher expression of NKG2A on NK cells. In viral inhibition assays, NaMiX initially increased viral replication of CD4+ T cells which was subsequently inhibited by cytotoxic NK cells. Importantly, anti-NKG2A NaMiX enhanced activation, cytotoxicity, IFN-γ production and CXCR5 expression of NK cells from HIV-1 positive individuals. In humanized NSG tg-huIL-15 mice, we confirmed enhanced activation, degranulation, cytotoxicity of NK cells, and killing of HIV-1 infected cells from mice injected with the anti-NKG2A.α NaMiX, as compared to control mice, as well as decreased total HIV-1 DNA in the lung.ConclusionsNK cell-mediated killing of HIV-1 infected cells by NaMiX represents a promising approach to support HIV-1 cure strategies.

Project description:BackgroundMetabolic reprogramming plays an essential role on lymphoma progression. Dysregulation of glutamine metabolism is implicated in natural-killer T-cell lymphoma (NKTCL) and tumor cell response to asparaginase-based anti-metabolic treatment.MethodsTo understand the metabolomic alterations and determine the potential therapeutic target of asparaginase, we assessed metabolomic profile using liquid chromatography-mass spectrometry in serum samples of 36 NKTCL patients, and integrated targeted metabolic analysis and RNA sequencing in tumor samples of 102 NKTCL patients. The biological function of solute carrier family 1 member 1 (SLC1A1) on metabolic flux, lymphoma cell growth, and drug sensitivity was further examined in vitro in NK-lymphoma cell line NK-92 and SNK-6, and in vivo in zebrafish xenograft models.FindingsIn NKTCL patients, serum metabolomic profile was characterized by aberrant glutamine metabolism and SLC1A1 was identified as a central regulator of altered glutaminolysis. Both in vitro and in vivo, ectopic expression of SLC1A1 increased cellular glutamine uptake, enhanced glutathione metabolic flux, and induced glutamine addiction, leading to acceleration of cell proliferation and tumor growth. Of note, SLC1A1 overexpression was significantly associated with PD-L1 downregulation and reduced cytotoxic CD3+/CD8+ T cell activity when co-cultured with peripheral blood mononuclear cells. Asparaginase treatment counteracted SLC1A1-mediated glutamine addiction, restored SLC1A1-induced impaired T-cell immunity. Clinically, high EAAT3 (SLC1A1-encoded protein) expression independently predicted superior progression-free and overall survival in 90 NKTCL patients treated with asparaginase-based regimens.InterpretationSLC1A1 functioned as an extracellular glutamine transporter, promoted tumor growth through reprogramming glutamine metabolism of NKTCL, while rendered tumor cells sensitive to asparaginase treatment. Moreover, SLC1A1-mediated modulation of PD-L1 expression might provide clinical rationale of co-targeting metabolic vulnerability and immunosuppressive microenvironment in NKTCL.FundingThis study was supported, in part, by research funding from the National Natural Science Foundation of China (82130004, 81830007 and 81900192), Chang Jiang Scholars Program, Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support (20152206 and 20152208), Clinical Research Plan of SHDC (2020CR1032B), Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine (DLY201601), Shanghai Chenguang Program (19CG15), Shanghai Sailing Program (19YF1430800), Medical-Engineering Cross Foundation of Shanghai Jiao Tong University (ZH2018QNA46), and Shanghai Yi Yuan Xin Xing Program.

Dataset Information

Combined analysis of bulk and single-cell RNA sequencing reveals novel natural killer cell-related prognostic biomarkers for predicting immunotherapeutic response in hepatocellular carcinoma.

Introduction

Methods

Results

Discussion

Publications

Combined analysis of bulk and single-cell RNA sequencing reveals novel natural killer cell-related prognostic biomarkers for predicting immunotherapeutic response in hepatocellular carcinoma.

Similar Datasets

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