PRMT5 orchestrates EGFR and AKT networks to activate NFκB and promote EMT DOI Open Access
Lei Huang,

Manasa Ravi,

Xiao‐Ou Zhang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 4, 2024

Neuroblastoma remains a formidable challenge in pediatric oncology, representing 15% of cancer-related mortalities children. Despite advancements combinatorial and targeted treatments improving survival rates, nearly 50% patients with high-risk neuroblastoma will ultimately succumb to their disease. Dysregulation the epithelial-mesenchymal transition (EMT) is key mechanism tumor cell dissemination, resulting metastasis poor outcomes many cancers. Our prior work identified PRMT5 as regulator EMT via methylation AKT at arginine 15, enhancing expression EMT-driving transcription factors facilitating metastasis. Here, we identify that directly regulates epidermal growth factor receptor (EGFR). PRMT5, through independent modulation EGFR pathways, orchestrates activation NFκB, upregulation pro-EMT ZEB1, SNAIL, TWIST1. Notably, form compensatory feedback loop, reinforcing these factors. Small molecule inhibition methyltransferase activity disrupts EGFR/AKT signaling, suppresses ablates vivo. findings underscore pivotal role control program neuroblastoma.

Language: Английский

Integrative analysis of neuroblastoma by single-cell RNA sequencing identifies the NECTIN2-TIGIT axis as a target for immunotherapy DOI Creative Commons
Judith Wienke, Lindy L. Visser, Waleed M. Kholosy

et al.

Cancer Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Pediatric patients with high-risk neuroblastoma have poor survival rates and urgently need more effective treatment options less side effects. Since novel improved immunotherapies may fill this need, we dissect the immunoregulatory interactions in by single-cell RNA-sequencing of 24 tumors (10 pre- 14 post-chemotherapy, including 5 pairs) to identify strategies for optimizing immunotherapy efficacy. Neuroblastomas are infiltrated natural killer (NK), T B cells, immunosuppressive myeloid populations. NK cells show reduced cytotoxicity a dysfunctional profile. Interaction analysis reveals vast network identifies NECTIN2-TIGIT as crucial immune checkpoint. Combined blockade TIGIT PD-L1 significantly reduces growth, complete responses (CR) vivo. Moreover, addition TIGIT+PD-L1 standard relapse chemotherapy-resistant Th-ALKF1174L/MYCN 129/SvJ syngeneic model induces CR. In conclusion, our integrative provides promising targets rationale immunotherapeutic combination strategies.

Language: Английский

Citations

35
Overcoming immunotherapy resistance in gastric cancer: insights into mechanisms and emerging strategies DOI Creative Commons

D.Y. Luo,

Jing Zhou, Shuiliang Ruan

et al.

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 7, 2025

Abstract Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with limited treatment options in advanced stages. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting PD1/PD-L1, has emerged as promising therapeutic approach. However, significant proportion patients exhibit primary or acquired resistance, limiting the overall efficacy immunotherapy. This review provides comprehensive analysis mechanisms underlying immunotherapy resistance GC, including role tumor microenvironment, dynamic PD-L1 expression, compensatory activation other checkpoints, and genomic instability. Furthermore, explores GC-specific factors such molecular subtypes, unique evasion mechanisms, impact Helicobacter pylori infection. We also discuss emerging strategies to overcome combination therapies, novel immunotherapeutic approaches, personalized based on genomics microenvironment. By highlighting these key areas, this aims inform future research directions clinical practice, ultimately improving outcomes for GC undergoing

Language: Английский

Citations

4
Divergent HLA variations and heterogeneous expression but recurrent HLA loss-of- heterozygosity and common HLA-B and TAP transcriptional silencing across advanced pediatric solid cancers DOI Creative Commons

Wan Ching Lim,

Maria Eugénia Marques Da Costa,

Karine Godefroy

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 22, 2024

The human leukocyte antigen (HLA) system is a major factor controlling cancer immunosurveillance and response to immunotherapy, yet its status in pediatric cancers remains fragmentary. We determined high-confidence HLA genotypes 576 children, adolescents young adults with recurrent/refractory solid tumors from the MOSCATO-01 MAPPYACTS trials, using normal tumor whole exome RNA sequencing data benchmarked algorithms. There was no evidence for narrowed allelic diversity but discordant homozygosity allele frequencies across types subtypes, such as embryonal alveolar rhabdomyosarcoma, neuroblastoma MYCN 11q high-grade glioma, several alleles may represent protective or susceptibility factors specific cancers. paucity of somatic mutations processing presentation (APP) genes most tumors, except cases mismatch repair deficiency genetic instability. prevalence loss-of-heterozygosity (LOH) ranged 5.9 7.7% class I 8.0 16.7% II genes, widely increased osteosarcoma glioblastoma (~15-25%), DRB1-DQA1-DQB1 Ewing sarcoma (~23-28%) low-grade glioma (~33-50%). HLA-DR expression assessed 194 44 patient-derived xenografts (PDXs) by immunochemistry, APP transcript levels quantified PDXs RT-qPCR. confirmed that heterogeneous advanced loss commonly associated transcriptional downregulation HLA-B transporter ( TAP ) whereas scarce on cells occurs immune infiltrating cells. Patients expressing sufficient some osteosarcoma, non-rhabdomyosarcoma soft-tissue more likely benefit T cell-based approaches, strategies upregulate expression, expand immunopeptidome, target TAP-independent epitopes possibly LOH might provide novel therapeutic opportunities others. consequences remain be established. Immunogenetic profiling should implemented routine inform immunotherapy trials precision medicine

Language: Английский

Citations

5
Unveiling the functional roles of patient‐derived tumour organoids in assessing the tumour microenvironment and immunotherapy DOI Creative Commons
Di Chen, Lixia Xu,

Mengjuan Xuan

et al.

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(9)

Published: Sept. 1, 2024

Language: Английский

Citations

4
Combining ERAP1 silencing and entinostat therapy to overcome resistance to cancer immunotherapy in neuroblastoma DOI Creative Commons
Patrizia Tempora, Silvia D’Amico, Paula Gragera

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: Oct. 22, 2024

Abstract Background Checkpoint immunotherapy unleashes tumor control by T cells, but it is undermined in non-immunogenic tumors, e.g. with low MHC class I expression and neoantigen burden, such as neuroblastoma (NB). Endoplasmic reticulum aminopeptidase 1 (ERAP1) an enzyme that trims peptides before loading on molecules. Inhibition of ERAP1 results the generation new antigens able inducing potent anti-tumor immune responses. Here, we identify a novel non-toxic combinatorial strategy based genetic inhibition administration HDAC inhibitor (HDACi) entinostat increase immunogenicity NB, making responsive to PD-1 therapy. Methods CRISPR/Cas9-mediated gene editing was used knockout (KO) 9464D NB cells derived from spontaneous tumors TH-MYCN transgenic mice. The PD-L1 evaluated flow cytometry (FC). immunopeptidome these studied mass spectrometry. Cocultures splenocytes bearing mice allowed assessment effect secretion inflammatory cytokines activation migration towards KO FC. Tumor cell killing Caspase 3/7 assay analysis. content analyzed FC, immunohistochemistry multiple immunofluorescence. Results We found makes more susceptible cell-mediated increasing both recall CD4 + CD8 NK cells. Treatment induces molecules vitro vivo. This pronounced changes induced inhibition, also restrains growth vivo remodelling tumor-infiltrating T-cell compartment. Interestingly, absence combination blockade overcomes resistance increases host survival. Conclusions These findings demonstrate combined HDACi treatment remodels landscape checkpoint immunotherapy.

Language: Английский

Citations

4
PMN-MDSCs are responsible for immune suppression in anti-PD-1 treated TAP1 defective melanoma DOI
Xiao Zhang,

Kaijun Sun,

Bingzheng Zhong

et al.

Clinical & Translational Oncology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 18, 2025

Language: Английский

Citations

0
Frizzled-7-targeting antibody-derived bifunctional protein retargets NK cells against triple-negative breast cancer cells via MICA-NKG2D axis DOI Creative Commons

Chenyue Wang,

Lisha Wu, Xingxing Li

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2025, Volume and Issue: 13(2), P. e009621 - e009621

Published: Feb. 1, 2025

Background Hypoxia is associated with the evasion of triple-negative breast cancer (TNBC) from immune surveillance. increases subpopulation putative TNBC stem-like cells (TNBCSCs) through activating Wnt/β-Catenin signaling. The shedding MHC class I-related chain A (MICA) particularly noteworthy in stem (CSCs), promoting resistance CSCs to natural killer (NK) cell cytotoxicity. To reestablish MICA/NKG2D-mediated immunosurveillance, we proposed design a fusion protein (SHH002-hu1-MICA) which consists Frizzled-7 (Fzd7)-targeting antibody and MICA, serving as an engager retargeting NK against TNBCs, especially TNBCSCs. Methods Opal multicolor immunohistochemistry staining was used validate expression membrane MICA (mMICA) existence tumors; flow cytometry (FCM) assay detect Fzd7/mMICA on TNBCs. Biolayer interferometry (BLI) surface plasmon resonance (SPR) assays were executed assess affinity SHH002-hu1-MICA towards rhFzd7/rhNKG2D; near-infrared imaging evaluate targeting capability. cytotoxicity conducted effects cell-mediated killing FCM analyze degranulation cells. Finally, cell-line-derived xenografts established anti-tumor activities vivo. Results mMICA significantly downregulated hypoxic TNBCs TNBCSCs, leading surveillance exerted by Fzd7 upregulated TNBCSCs exhibits negative correlation infiltration level On accurate assembly, shows strong for rhFzd7/rhNKG2D, specifically targets tumor tissues, disrupts enhances inducing promotes CD44 high regions within xenograft tumors, exhibiting superior than SHH002-hu1. Conclusions maintains property SHH002-hu1, successfully activates retargets antitumor represents promising new cell-based immunotherapy TNBC.

Language: Английский

Citations

0
Harnessing Histone Deacetylase Inhibitors for Enhanced Cancer Immunotherapy DOI

Fatemeh Hedayat,

Elnaz Faghfuri

European Journal of Pharmacology, Journal Year: 2025, Volume and Issue: 997, P. 177620 - 177620

Published: April 14, 2025

Language: Английский

Citations

0
Targeting the HLA-E–NKG2A axis in combination with MS-275 enhances NK cell-based immunotherapy against DMG DOI Creative Commons
Yuxuan Deng,

Jinqiu Liu,

Zhuonan Pu

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2025, Volume and Issue: 44(1)

Published: April 29, 2025

Abstract Background Diffuse midline glioma (DMG) is an aggressive pediatric brain tumor with limited treatment options. Although natural killer (NK) cell-based immunotherapy promising, its efficacy remains limited, necessitating strategies to enhance NK cell cytotoxicity. Histone deacetylase (HDAC) inhibition demonstrate potential NK-mediated killing. However, the combination of HDAC inhibitors and therapy for DMG unexplored. Methods Patient-derived lines orthotopic mouse models were used evaluate effects class I inhibitor MS-275 on cell-mediated lysis was measured using both luciferase calcein AM-based assays. The downstream signaling pathways affected by investigated via RNA-seq, CUT&Tag assay, RT‒qPCR, chromatin immunoprecipitation qPCR. Results Based bioinformatic analysis, HDACs are identified as therapeutic targets in DMG. corresponding inhibitor, upregulated cytotoxicity pathway through GSEA analysis. Pretreating cells elevated ligand gene expression enhanced cell-induced lysis. In addition NK-activating ligands, NK-inhibitory HLA-E, thereby enhancing immunotherapies targeting NKG2A–HLA-E axis. Mechanistically, increased HLA-E promoting STAT3 acetylation at lysine 685. Combining blockade axis extended overall survival models. Conclusions This study first that enhances represents a promising strategy treating

Language: Английский

Citations

0
Three-Dimensional Culture Systems in Neuroblastoma Research DOI Creative Commons
Piotr Jung, Adam J. Wolpaw

Organoids, Journal Year: 2025, Volume and Issue: 4(2), P. 10 - 10

Published: May 8, 2025

Basic and translational cancer biology research requires model systems that recapitulate the features of human tumors. While two-dimensional (2D) cell cultures have been foundational allowed critical advances, they lack organizational complexity, cellular interactions, extracellular matrix present in vivo. Mouse models thus remained gold standard for studying cancer. In addition to high cost low throughput, mouse can also suffer from reduced tumor heterogeneity species-specific differences. Three-dimensional (3D) culture emerged as a key intermediary between 2D lines models, with lower greater flexibility than more accurate representation microenvironment lines. neuroblastoma, an aggressive childhood cancer, 3D applied study drug responses, motility, tumor–matrix interactions. Recent advances include integration immune cells immunotherapy studies, mesenchymal stromal tumor–stroma bioprinted manipulate properties. This review examines use highlighting their advantages limitations while emphasizing potential bridge gaps vitro, preclinical, clinical applications. By improving our understanding neuroblastoma biology, hold promise advancing therapeutic strategies outcomes this

Language: Английский

Citations

0