B4GALT1 promotes immune escape by regulating the expression of PD-L1 at multiple levels in lung adenocarcinoma

Journal of Experimental & Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 42(1)

Published: June 12, 2023

Abstract Background Invasive adenocarcinoma (IAC), which is typically preceded by minimally invasive (MIA), the dominant pathological subtype of early-stage lung (LUAD). Identifying molecular events underlying progression from MIA to IAC may provide a crucial perspective and boost exploration novel strategies for LUAD diagnosis treatment. Methods Transcriptome sequencing four pairs tumours obtained multiple primary cancer patients was performed screen out beta-1,4-galactosyltransferase1 ( B4GALT1 ). Function mechanism experiments in vitro vivo were explore regulatory -mediated immune evasion regulating programmed cell death ligand 1 (PD-L1). Results , key gene involved N-glycan biosynthesis, highly expressed samples. Further revealed that regulated proliferation invasion both related impaired antitumour capacity CD8 + T cells. Mechanistically, directly mediates N-linked glycosylation PD-L1 protein, thus preventing degradation at posttranscriptional level. In addition, stabilized TAZ protein via glycosylation, activated CD274 transcriptional These factors lead escape. Importantly, inhibition increased T-cell abundance activity enhanced immunity anti-PD-1 therapy vivo. Conclusion critical molecule development be target intervention immunotherapy.

Language: Английский

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The role of N-glycosylation modification in the pathogenesis of liver cancer

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(3)

Published: March 29, 2023

Abstract N-glycosylation is one of the most common types protein modifications and it plays a vital role in normal physiological processes. However, aberrant N-glycan are closely associated with pathogenesis diverse diseases, including processes such as malignant transformation tumor progression. It known that conformation glycoproteins altered during different stages hepatocarcinogenesis. Characterizing heterogeneity biological functions glycans liver cancer patients will facilitate deeper understanding molecular mechanisms injury In this article, we review hepatocarcinogenesis, focusing on epithelial-mesenchymal transition, extracellular matrix changes, microenvironment formation. We highlight its potential applications treatment or diagnosis cancer.

Language: Английский

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Glycosylation shapes the efficacy and safety of diverse protein, gene and cell therapies

Biotechnology Advances, Journal Year: 2023, Volume and Issue: 67, P. 108206 - 108206

Published: June 22, 2023

Over recent decades, therapeutic proteins have had widespread success in treating a myriad of diseases. Glycosylation, near universal feature this class drugs, is critical quality attribute that significantly influences the physical properties, safety profile and biological activity proteins. Optimizing protein glycosylation, therefore, offers an important avenue to developing more efficacious therapies. In review, we discuss specific examples how variations glycan structure glycoengineering impacts stability, safety, clinical efficacy protein-based drugs are already market as well those still preclinical development. We also highlight impact glycosylation on next generation biologics such T cell-based cancer therapy gene therapy.

Language: Английский

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Unconventional secretion of unglycosylated ORF8 is critical for the cytokine storm during SARS-CoV-2 infection

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(1), P. e1011128 - e1011128

Published: Jan. 23, 2023

Coronavirus disease 2019 is a respiratory infectious caused by the severe acute syndrome coronavirus 2 (SARS-CoV-2). Evidence on pathogenesis of SARS-CoV-2 accumulating rapidly. In addition to structural proteins such as Spike and Envelope, functional roles non-structural accessory in regulating viral life cycle host immune responses remain be understood. Here, we show that open reading frame 8 (ORF8) acts messenger for inter-cellular communication between alveolar epithelial cells macrophages during infection. Mechanistically, ORF8 secretory protein can secreted infected via both conventional unconventional pathways. Conventionally glycosylated loses ability recognize interleukin 17 receptor A macrophages, possibly due steric hindrance imposed N-glycosylation at Asn78. However, unconventionally does not undergo glycosylation without experiencing ER-Golgi trafficking, thereby activating downstream NF-κB signaling pathway facilitating burst cytokine release. Furthermore, deletion attenuates inflammation yields less lung lesions hamsters. Our data collectively highlights role development storms

Language: Английский

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CD276 regulates the immune escape of esophageal squamous cell carcinoma through CXCL1–CXCR2 induced NETs

Journal for ImmunoTherapy of Cancer, Journal Year: 2024, Volume and Issue: 12(5), P. e008662 - e008662

Published: May 1, 2024

Background CD276 (B7-H3), a pivotal immune checkpoint, facilitates tumorigenicity, invasiveness, and metastasis by escaping surveillance in variety of tumors; however, the underlying mechanisms facilitating escape esophageal squamous cell carcinoma (ESCC) remain enigmatic. Methods We investigated expression ESCC tissues from patients using immunohistochemistry (IHC) assays. In vivo, we established 4-nitroquinoline 1-oxide (4NQO)-induced knockout (CD276 wKO ) K14cre; conditional cKO mouse model to study functional role ESCC. Furthermore, used 4NQO-induced evaluate effects anti-CXCL1 antibodies, anti-Ly6G anti-NK1.1 GSK484 inhibitors on tumor growth. Moreover, IHC, flow cytometry, immunofluorescence techniques were employed measure proportions addition, conducted single-cell RNA sequencing analysis examine alterations microenvironment following depletion. Results this study, elucidate that is markedly upregulated ESCC, correlating with poor prognosis. our results indicate depletion inhibits tumorigenesis progression epithelial cells engenders significant downregulation CXCL1, consequently reducing formation neutrophil extracellular trap networks (NETs) via CXCL1–CXCR2 signaling axis, while simultaneously augmenting natural killer (NK) cells. overexpression promotes increasing NETs’ NK vivo. Conclusions This successfully elucidates Our comprehensive uncovers modulating thereby suggesting targeting might serve as potential therapeutic approach for treatment.

Language: Английский

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Targeting branched N-glycans and fucosylation sensitizes ovarian tumors to immune checkpoint blockade

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 2, 2024

Abstract Aberrant glycosylation is a crucial strategy employed by cancer cells to evade cellular immunity. However, it’s unclear whether homologous recombination (HR) status-dependent can be therapeutically explored. Here, we show that the inhibition of branched N -glycans sensitizes HR-proficient, but not HR-deficient, epithelial ovarian cancers (EOCs) immune checkpoint blockade (ICB). In contrast fucosylation whose EOCs anti-PD-L1 immunotherapy regardless HR-status, observe an enrichment on HR-proficient compared HR-deficient EOCs. Mechanistically, BRCA1/2 transcriptionally promotes expression MGAT5, enzyme responsible for catalyzing -glycans. The tumors augment their resistance enhancing its binding with PD-1 CD8 + T cells. orthotopic, syngeneic EOC models in female mice, inhibiting using 2-Deoxy-D-glucose EOCs, anti-PD-L1. These findings indicate as promising therapeutic targets ICB overcoming evasion.

Language: Английский

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Altered glycosylation in cancer: molecular functions and therapeutic potential

Cancer Communications, Journal Year: 2024, Volume and Issue: 44(11), P. 1316 - 1336

Published: Sept. 21, 2024

Abstract Glycosylation, a key mode of protein modification in living organisms, is critical regulating various biological functions by influencing folding, transportation, and localization. Changes glycosylation patterns are significant feature cancer, associated with range pathological activities cancer‐related processes, serve as biomarkers providing new targets for cancer diagnosis treatment. Glycoproteins like human epidermal growth factor receptor 2 (HER2) breast alpha‐fetoprotein (AFP) liver carcinoembryonic antigen (CEA) colon prostate‐specific (PSA) prostate all tumor approved clinical use. Here, we introduce the diversity structures newly discovered substrate—glycosylated RNA (glycoRNA). This article focuses primarily on metastasis, immune evasion, metabolic reprogramming, aberrant ferroptosis responses, cellular senescence to illustrate role cancer. Additionally, summarize applications diagnostics, treatment, multidrug resistance. We envision promising future glycosylation.

Language: Английский

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Regulation of PD-L1 glycosylation and advances in cancer immunotherapy

Cancer Letters, Journal Year: 2025, Volume and Issue: unknown, P. 217498 - 217498

Published: Jan. 1, 2025

Language: Английский

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Lipid Nanoparticle Delivery System for mRNA Encoding B7H3‐redirected Bispecific Antibody Displays Potent Antitumor Effects on Malignant Tumors

Advanced Science, Journal Year: 2022, Volume and Issue: 10(3)

Published: Nov. 20, 2022

The therapeutic use of bispecific T-cell engaging (BiTE) antibodies has shown great potential for treating malignancies. BiTE can simultaneously engage CD3ε on T cells and tumor antigen cancer cells, thus exerting an effective antitumor effect. Nevertheless, challenges in production, manufacturing, short serum half-life have dampened some the promise impeded pace BiTE-based therapeutics to combat diseases. Nowadays, vitro-transcribed mRNA achieved programmed which is more flexible cost-effective than traditional method producing recombinant antibody. Here, authors developed a treatment by encapsulating encoding B7H3×CD3 into novel ionizable lipid nanoparticles (LNPs). found that LNPs high transfection efficiency, hepatosplenic targeting capability produce concentrations BiTE. Above all, single intravenous injection mRNA-LNPs could achieve levels protein expression vivo significantly prolonged BiTE, elicit robust durable efficacy against hematologic malignancies melanoma. Therefore, their results suggested strategy based research value promising clinical application prospects.

Language: Английский

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L‐fucose, a sugary regulator of antitumor immunity and immunotherapies

Molecular Carcinogenesis, Journal Year: 2022, Volume and Issue: 61(5), P. 439 - 453

Published: Feb. 2, 2022

Abstract l ‐fucose is a dietary sugar that used by cells in process called fucosylation to posttranslationally modify and regulate protein behavior function. As plays essential cellular functions normal organ immune developmental homeostasis, it perhaps not surprising has been found be perturbed number of pathophysiological contexts, including cancer. Increasing studies over the years have highlighted key roles altered can play cancer cell‐intrinsic as well paracrine signaling interactions. In particular, demonstrated impact tumor:immunological interactions significantly enhance or attenuate antitumor immunity. Importantly, appears posttranslational modification therapeutically targeted, manipulating molecular underpinnings shown sufficient impair block tumor progression modulate Moreover, anticancer agents, such therapeutic antibodies, critically their efficacy. this review, we summarize underappreciated cells, antibodies manipulation implications new modalities for

Language: Английский

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