IL-1RAP, a Key Therapeutic Target in Cancer

Frenay, Jame; Bellaye, Pierre-Simon; Oudot, Alexandra; Helbling, Alex; Petitot, Camille; Ferrand, Christophe; Collin, Bertrand; Dias, A.

doi:10.3390/ijms232314918

Cited by 7 publications

(3 citation statements)

References 157 publications

(195 reference statements)

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“…Studies have revealed that peptidoglycan, lipoprotein, mycoplasma lipopeptides, flagellin, CpG DNA and double-stranded RNA specifically bind and activate TLRs, thereby inducing IκBζ production ( 49 , 50 ). IL-1 superfamily members are often classified into four subfamilies based on the coreceptors that they bind: the IL-1, IL-33, and IL-36 subfamilies, whose members function in conjunction with the coreceptor IL-1RAP, and the IL-18 subfamily, which members bind a different coreceptor ( 51 ). In IL-1β-treated primary chondrocytes, NFKBIZ is one of the most significantly upregulated genes ( 39 ).…”

Section: Iκbζ Is Induced Via Inflammatory Signal P...mentioning

confidence: 99%

The central inflammatory regulator IκBζ: induction, regulation and physiological functions

Feng

Chen

et al. 2023

Front. Immunol.

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IκBζ (encoded by NFKBIZ) is the most recently identified IkappaB family protein. As an atypical member of the IkappaB protein family, NFKBIZ has been the focus of recent studies because of its role in inflammation. Specifically, it is a key gene in the regulation of a variety of inflammatory factors in the NF-KB pathway, thereby affecting the progression of related diseases. In recent years, investigations into NFKBIZ have led to greater understanding of this gene. In this review, we summarize the induction of NFKBIZ and then elucidate its transcription, translation, molecular mechanism and physiological function. Finally, the roles played by NFKBIZ in psoriasis, cancer, kidney injury, autoimmune diseases and other diseases are described. NFKBIZ functions are universal and bidirectional, and therefore, this gene may exert a great influence on the regulation of inflammation and inflammation-related diseases.

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Section: Iκbζ Is Induced Via Inflammatory Signal P...mentioning

confidence: 99%

The central inflammatory regulator IκBζ: induction, regulation and physiological functions

Feng

Chen

et al. 2023

Front. Immunol.

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“…IL1RAP is a crucial co-receptor expressed in numerous tissues and cell types, emphasizing its pivotal role in immune responses, cancers, and infectious diseases (38). The IL1RAP serves as a subunit to the type I IL-1 receptor (IL-1RI), a specific plasma membrane receptor, which facilitates the transmission of numerous biological effects of the pro-inflammatory cytokine IL-1 on an array of target cells (39, 40).…”

Section: Discussionmentioning

confidence: 99%

Unveiling the pathogenesis of non-alcoholic fatty liver disease by decoding biomarkers through integrated single-cell and single-nucleus profiles

Ma,

Zhong,

Cai

et al. 2023

Preprint

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Background and AimsNon-alcoholic fatty liver disease (NAFLD) is a heterogenous liver disease encompassing pathological changes ranging from simple steatosis, inflammation and fibrosis to cirrhosis. To further unravel NAFLD pathogenesis, we aimed to decode the candidate NAFLD biomarkers associated with NAFLD severity using publicly available single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) data.MethodsSeurat v5 and anchor-based reciprocal principal components analysis (RPCA) integration were performed to integrate and analyze the scRNA-seq and snRNA-seq data of 82 liver and Peripheral Blood Mononuclear Cell (PBMC) specimens from NAFLD patients and healthy controls to decode the candidate NAFLD biomarkers generated previously. Using the ‘CellChat’ R package, we analyzed ligand-receptor interactions of our candidate biomarkers from secreted genes to understand their signaling crosstalk and implications in NAFLD’s biological processes.ResultsWe generated a database (https://dreamapp.biomed.au.dk/NAFLD-scRNA-seq/) to present the NAFLD pathogenesis by analyzing integrated scRNA-seq and snRNA-seq data. Through cell-level decoding, we discovered the expression distribution of the candidate biomarkers associated with NAFLD severity. The analysis of ligand-receptor pairs in NAFLD liver and PBMC data suggests that the IL1B-(IL1R1+IL1RAP) interaction between liver monocytes and hepatocytes/cholangiocytes may explain the correlation between NAFLD severity and IL1RAP down-regulation.ConclusionsWe confirmed a strong correlation between liver QSOX1/IL1RAP concentrations and NAFLD severity at the cellular level. Additionally, our analysis of comprehensive data unveiled new aspects of NAFLD pathogenesis and intercellular communication through the use of scRNA and snRNA sequencing data. (ChiCTR2300073940).Lay SummaryWe integrated single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) data to unravel non-alcoholic fatty liver disease (NAFLD) pathogenesis. We decoded candidate biomarkers associated with NAFLD progression, which were previously screened from RNA sequencing (RNA-seq) data of 625 liver samples with a novel gene clustering method. A new version of the R package ‘’Seurat v5’ and anchor-based reciprocal principal components analysis (RPCA) integration were performed to process and integrate scRNA-seq and snRNA-seq data of 82 liver and Peripheral Blood Mononuclear Cell (PBMC) specimens from NAFLD patients and healthy controls. The research delved deeper into the cellular expression patterns of the candidate biomarkers and examined the intercellular communication of their secreted signaling.Graphical abstractHighlightsIntegrated single-cell and single-nucleus profiles from 82 liver and PBMC specimens comprising NAFLD patients and healthy controls with increasing severity were utilized to unveil the NAFLD pathogenesis through decoding candidate biomarkers of NAFLD.In cell-level observations, we decoded 16 up-regulated and 22 down-regulated secreting genes previously identified as associated with increasing NAFLD severity in the liver RNA-seq and plasma proteomics data.QSOX1, enriched in fibroblasts, and IL1RAP, enriched in hepatocytes, have been further validated and interpreted in integrated single-cell and single-nucleus profiles for their potential to predict NAFLD severity.The analysis of intercellular crosstalk, focusing on secreted signaling from our previously identified candidate biomarkers sourced from secreted genes, highlighted the IL1B-(IL1R1+IL1RAP) pathway between liver monocytes and hepatocytes/cholangiocytes. This suggests that this pathway might be a potential reason for the observed downregulation of IL1RAP in NAFLD liver.

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“…In the past years, CD19 ( 211 , 212 ), CD26 ( 213 ), CD38 ( 214 ), and IL-1-Receptor-associated Protein (IL-1-RAP) ( 215 ) have been investigated as potential target antigens for a CAR-T-cell therapy approach in CML. IL-1-RAP is of pronounced interest as its expression correlates with the formation of the Philadelphia chromosome in CML cells ( 216 ) and is often expressed in increased levels on malignant hematopoietic cells ( 217 ). CAR-T cells targeting IL-1-RAP can be produced semi-automatically and GMP-compliant since 2023 ( 218 ).…”

Section: Chronic Myeloid Leukemiamentioning

confidence: 99%

Broadening the horizon: potential applications of CAR-T cells beyond current indications

Karsten,

Matrisch,

Cichutek

et al. 2023

Front. Immunol.

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Engineering immune cells to treat hematological malignancies has been a major focus of research since the first resounding successes of CAR-T-cell therapies in B-ALL. Several diseases can now be treated in highly therapy-refractory or relapsed conditions. Currently, a number of CD19- or BCMA-specific CAR-T-cell therapies are approved for acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), multiple myeloma (MM), and follicular lymphoma (FL). The implementation of these therapies has significantly improved patient outcome and survival even in cases with previously very poor prognosis. In this comprehensive review, we present the current state of research, recent innovations, and the applications of CAR-T-cell therapy in a selected group of hematologic malignancies. We focus on B- and T-cell malignancies, including the entities of cutaneous and peripheral T-cell lymphoma (T-ALL, PTCL, CTCL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), classical Hodgkin-Lymphoma (HL), Burkitt-Lymphoma (BL), hairy cell leukemia (HCL), and Waldenström’s macroglobulinemia (WM). While these diseases are highly heterogenous, we highlight several similarly used approaches (combination with established therapeutics, target depletion on healthy cells), targets used in multiple diseases (CD30, CD38, TRBC1/2), and unique features that require individualized approaches. Furthermore, we focus on current limitations of CAR-T-cell therapy in individual diseases and entities such as immunocompromising tumor microenvironment (TME), risk of on-target-off-tumor effects, and differences in the occurrence of adverse events. Finally, we present an outlook into novel innovations in CAR-T-cell engineering like the use of artificial intelligence and the future role of CAR-T cells in therapy regimens in everyday clinical practice.

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IL-1RAP, a Key Therapeutic Target in Cancer

Cited by 7 publications

References 157 publications

The central inflammatory regulator IκBζ: induction, regulation and physiological functions

The central inflammatory regulator IκBζ: induction, regulation and physiological functions

Unveiling the pathogenesis of non-alcoholic fatty liver disease by decoding biomarkers through integrated single-cell and single-nucleus profiles

Broadening the horizon: potential applications of CAR-T cells beyond current indications

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