PBRM1 and the glycosylphosphatidylinositol biosynthetic pathway promote tumor killing mediated by MHC-unrestricted cytotoxic lymphocytes

Menasche, Bridget L.; Davis, Eric M.; Wang, Shifeng; Ouyang, Yu; Li, Suzhao; Yu, Haijia; Shen, Jingshi

doi:10.1126/sciadv.abc3243

Cited by 12 publications

(6 citation statements)

References 65 publications

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“…The previous study con rmed that the activation and cytolytic granule secretion of cytotoxic lymphocytes (CLs) necessitate the presence of the glycosylphosphatidylinositol (GPI) biosynthetic pathway (59).…”

Section: Discussionmentioning

confidence: 99%

Targeting N4BP2L1 for Therapy in IPF and SSc-ILD: Evidence from Mendelian Randomization and Multi-Omics Analysis

Lv,

Tang,

et al. 2024

Preprint

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Background: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) and idiopathic pulmonary fibrosis (IPF) are paradigmatic conditions characterized by similar pathogenic mechanisms involving inflammation and fibrosis. Both disorders present considerable challenges due to their elevated mortality rates and the difficulty in identifying effective treatments. Consequently, it is imperative to explore potential targets and deepen our understanding of the initiation and progression of these diseases. Methods: To address this, we utilized a combination of Mendelian randomization (MR) analysis, single-cell RNA sequencing (scRNA-seq) analysis, and other multi-omics analysis. Results: Our investigation confirmed the involvement of N4BP2L1 in CD8+ effector T (Teff) cells and its causal relationship with SSc-ILD. Subsequent multi-omics analyses were conducted to validate the role of N4BP2L1+ CD8+ Teff cells in the pathogenesis of both IPF and SSc-ILD. Through enrichment analysis, we unveiled the complex interplay among programmed necrosis, autophagy, and ferroptosis, highlighting their pivotal role in modulating the activity of N4BP2L1+ CD8+ Teff cells. Conclusions: In essence, the heightened activity of N4BP2L1+ CD8+ Teff cells is implicated in the development of inflammation, fibrosis, and epithelial-mesenchymal transition (EMT), emphasizing its significance in the pathogenesis of both SSc-ILD and IPF.

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Section: Discussionmentioning

confidence: 99%

Targeting N4BP2L1 for Therapy in IPF and SSc-ILD: Evidence from Mendelian Randomization and Multi-Omics Analysis

Lv,

Tang,

et al. 2024

Preprint

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“…It was expected TALL-104 coculture would not be cytotoxic as myotubes should lack epitopes that trigger cytotoxicity. Furthermore, TALL-104 spare normal cells whilst targeting tumourigenic cells 57 – 60 . NK cells can target autologous skeletal muscle cultures from healthy patients, whilst autologous myotubes were not targeted or killed by CD8 cytotoxic T cells 61 .…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic immune cells do not affect TDP-43 and p62 sarcoplasmic aggregation but influence TDP-43 localisation

McCord,

Day

2023

Sci Rep

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Sporadic inclusion body myositis (sIBM) is an idiopathic inflammatory myopathy with invasion of CD8 T cells in muscle and aggregation of proteins in the sarcoplasm. TDP-43 and p62 are two proteins that aggregate in affected muscle, and have been suggested as specific markers for sIBM over other inflammatory myopathies. TDP-43 is also mislocalised from the nucleus to the sarcoplasm in sIBM. It is not clear if inflammation precedes protein aggregation in sIBM. This study investigated if exposure to cytotoxic inflammatory cells caused TDP-43 and p62 aggregation or TDP-43 mislocalisation in cultured myotubes. TALL-104 coculture was highly cytotoxic to myotubes after 24 h. Secretion of IFNγ and TNFα were higher in cocultures compared to monocultured TALL-104 cells, indicating activation. TALL-104 cells attached to and infiltrated myotubes. There was no effect of TALL-104 coculture on TDP-43 or p62 sarcoplasmic aggregate size or frequency. However, there was decreased localisation of TDP-43 to the nucleus with TALL-104 coculture compared to control. In an in vitro setting, cytotoxic immune cells did not cause TDP-43 or p62 sarcoplasmic aggregation, suggesting cellular cytotoxicity may not trigger aggregation of these proteins. However TALL-104 coculture influenced TDP-43 localisation, suggesting cytotoxic immune cells may contribute to TDP-43 localisation shifts which is observed in sIBM.

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“…Mutations in VHL are among the most frequently observed in ccRCC, and it has been established that the suppression, removal, or methylation of VHL promotes tumorigenesis and cancer progression [ 37 ]. Mutations in the PBRM1 gene have been shown to contribute to the development of tumors by inhibiting the ability of natural killer cells to clear tumor cells [ 38 ]. A deficit of SETD2 promotes tumorigenesis through the activation of oncogenic transcription [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Establishment of a Seven-Gene Signature Associated with CD8+ T Cells through the Utilization of Both Single-Cell and Bulk RNA-Sequencing Techniques in Clear Cell Renal Cell Carcinoma

Chen,

Zhou,

Xie

et al. 2023

IJMS

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Tumor immune microenvironment constituents, such as CD8+ T cells, have emerged as crucial focal points for cancer immunotherapy. Given the absence of reliable biomarkers for clear cell renal cell carcinoma (ccRCC), we aimed to ascertain a molecular signature that could potentially be linked to CD8+ T cells. The differentially expressed genes (DEGs) linked to CD8+ T cells were identified through an analysis of single-cell RNA sequencing (scRNA-seq) data obtained from the Gene Expression Omnibus (GEO) database. Subsequently, immune-associated genes were obtained from the InnateDB and ImmPort datasets and were cross-referenced with CD8+ T-cell-associated DEGs to generate a series of DEGs linked to immune response and CD8+ T cells. Patients with ccRCC from the Cancer Genome Atlas (TCGA) were randomly allocated into testing and training groups. A gene signature was established by conducting LASSO-Cox analysis and subsequently confirmed using both the testing and complete groups. The efficacy of this signature in evaluating immunotherapy response was assessed on the IMvigor210 cohort. Finally, we employed various techniques, including CIBERSORT, ESTIMATE, ssGSEA, and qRT-PCR, to examine the immunological characteristics, drug responses, and expression of the signature genes in ccRCC. Our findings revealed 206 DEGs linked to immune response and CD8+ T cells, among which 65 genes were correlated with overall survival (OS) in ccRCC. A risk assessment was created utilizing a set of seven genes: RARRES2, SOCS3, TNFSF14, XCL1, GRN, CLDN4, and RBP7. The group with a lower risk showed increased expression of CD274 (PD-L1), suggesting a more favorable response to anti-PD-L1 treatment. The seven-gene signature demonstrated accurate prognostic prediction for ccRCC and holds potential as a clinical reference for treatment decisions.

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PBRM1 and the glycosylphosphatidylinositol biosynthetic pathway promote tumor killing mediated by MHC-unrestricted cytotoxic lymphocytes

Cited by 12 publications

References 65 publications

Targeting N4BP2L1 for Therapy in IPF and SSc-ILD: Evidence from Mendelian Randomization and Multi-Omics Analysis

Targeting N4BP2L1 for Therapy in IPF and SSc-ILD: Evidence from Mendelian Randomization and Multi-Omics Analysis

Cytotoxic immune cells do not affect TDP-43 and p62 sarcoplasmic aggregation but influence TDP-43 localisation

Establishment of a Seven-Gene Signature Associated with CD8+ T Cells through the Utilization of Both Single-Cell and Bulk RNA-Sequencing Techniques in Clear Cell Renal Cell Carcinoma

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