Glycoconjugates: Synthesis, Functional Studies, and Therapeutic Developments

Chemical Reviews, Journal Year: 2022, Volume and Issue: 122(20), P. 15603 - 15671

Published: Sept. 29, 2022

Glycoconjugates are major constituents of mammalian cells that formed via covalent conjugation carbohydrates to other biomolecules like proteins and lipids often expressed on the cell surfaces. Among three classes glycoconjugates, proteoglycans glycoproteins contain glycans linked protein backbone amino acid residues such as Asn for N-linked Ser/Thr O-linked glycans. In glycolipids, a lipid component glycerol, polyisoprenyl pyrophosphate, fatty ester, or sphingolipid. Recently, glycoconjugates have become better structurally defined biosynthetically understood, especially those associated with human diseases, accessible new drug, diagnostic, therapeutic developments. This review describes status advances in biological study applications natural synthetic including proteoglycans, glycoproteins, glycolipids. The scope, limitations, novel methodologies synthesis clinical development vaccines, glyco-remodeled antibodies, glycan-based adjuvants, glycan-specific receptor-mediated drug delivery platforms, etc., their future prospectus discussed.

Language: Английский

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Aberrant protein glycosylation: Implications on diagnosis and Immunotherapy

Biotechnology Advances, Journal Year: 2023, Volume and Issue: 66, P. 108149 - 108149

Published: April 6, 2023

Glycosylation-mediated post-translational modification is critical for regulating many fundamental processes like cell division, differentiation, immune response, and cell-to-cell interaction. Alterations in the N-linked or O-linked glycosylation pattern of regulatory proteins transcription factors cellular receptors lead to diseases, including cancer. These alterations give rise micro- macro-heterogeneity tumor cells. Here, we review role O- its function autoimmunity aberrant The change glycome could result from a expression glycosidases glycosyltransferases N-acetyl-glucosaminyl transferase V, FUT8, ST6Gal-I, DPAGT1, etc., impact target leading transformation. Moreover, mutations glycogenes affect patterns on cells other related manifestations pro- anti-inflammatory effects. In recent years, understanding cancer indicates that it can be utilized both diagnosis/prognosis as well immunotherapy. Studies involving mass spectrometry proteome, site- structure-specific glycoproteomics, transcriptomics/genomics patient samples models revealed importance homeostasis biology. development emerging technologies, such lectin microarray, has facilitated research structure glycans glycosylation. Newly developed devices allow high-throughput, high-speed, precise This paper also discusses technologies clinical applications

Language: Английский

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Introduction to checkpoint inhibitors and cancer immunotherapy

Immunological Reviews, Journal Year: 2017, Volume and Issue: 276(1), P. 5 - 8

Published: March 1, 2017

This article introduces a series of reviews covering Checkpoint Inhibitors and Cancer Immunotherapy appearing in Volume 276 Immunological Reviews. Immune responses are regulated by an exquisite system checks balances that enable effective protective immunity tolerance. A number immunological checkpoints control cells the innate adaptive immune determine their function. Stimulatory checkpoint pathways promote activation naive T cells, as well effector, memory regulatory cell responses. Inhibitory limit threshold for duration responses, have diverse effects regulate resolution inflammation, tolerance homeostasis. Tumors hijacked inhibitory to evade eradication. Blockade inhibitors CTLA-4 PD-1 has shown remarkably durable clinical but is only subset patients.1-5 Combination therapy approaches further improving response rates.6 These successes stimulated great interest determining roles controlling immunosuppressive tumor microenvironment, developing strategies target these cancer immunotherapy. Reviews this issue discuss immunoregulatory pathogenesis cancer, autoimmune diseases, graft rejection. In introduction, I will provide overview issue. Insights into mechanisms regulating led development blockade therapy. Our knowledge progressed significantly from two-signal concept activation, proposed Lafferty Cunningham explain cells.7-9 According model, requires first signal provided interaction antigenic peptide/MHC complex with receptor (TCR), which confers specificity response, second antigen-independent costimulatory signal. The between CD28 its ligands CD80 (B7-1) CD86 (B7-2) fulfilled many requirements envisioned (see 10 issue). However, discovery homolog possessed potent functions, dramatically changed our perception two model.10-13 We now appreciate there (coinhibitory) stimulatory (costimulatory) signals can modulate (TCR)—mediated signals. tune shape activating safeguard homeostasis protect against immune-mediated tissue damage. addition, key mediators dysfunction (exhaustion) develops during thereby prevents anti-tumor immunity. critical role illustrated remarkable cancer.1, 5, 14 Seminal studies showing anti-CTLA-4 blocking antibodies could mouse models15 antibody ipilimumab FDA approval melanoma. most striking effect ability induce long-lasting regression.4 pathway impressive trial results 30%-50% rates broad range tumors, approved melanoma, non-small lung kidney Hodgkin Disease, head neck, bladder cancer.2, 3, 14, 16, 17 There identifying extend benefit more patients. success anti-PD-1 immunotherapy search other molecules reviewed (Figure 1) therapeutic targets coinhibitory fall major families, Ig superfamily includes CD28, ICOS,10 TMIGD2 (IGPR-1/CD28H)18 (which family members) CD226,19 TNF:TNR family, Ox40 4-1BB.10 abundance influence include B7: members CTLA-4, PD-1/PD-L, B7-H3 (CD276),18, 20 B7-H4 (B7x/B7S1/VTCN1),18, 20, 21 HHLA2 (B7H7/B7-H5)18 VISTA (PD-1H, DD1alpha, c10orf54, Gi24, Dies1, SISP1),20, 22 LAG-3,23 TIGIT CD96,19 ectonucleotidases CD39 CD7324 TIM-3 (T cell–immunoglobulin–mucin domain 3)25 mucin domains. focus on functions translation Similar express initiate responses.26-28 APCs mediate recruitment through antigen recognition, acquisition, processing presentation expression ligands, production variety effector molecules. expressed inhibit activity Given stimulate or dampen immunity, growing enhance CD47,27 TAM tyrosine kinases (Tyro, Axl MerTK)26 Siglecs28 potential demonstrate significant recent advances understanding checkpoints. progress provides foundation tremendous discovering immunotherapies regulators microenvironment. important questions remain be resolved address challenges translating First, work needed understand extent redundant unique whether hierarchy orchestration For example, receptors coexpressed coblockade CTLA-4,13 Tim-3,25 23 TIGIT,19 Vista20, lead better clearance than each alone. It not yet clear synergy same different cells. molecular triggered shared signaling nodes, pathways. Second, cell-type specific beginning understood. increasing appreciation opposing modulators cells.10 poses strategies, need all subpopulations, both regulatory.10 Some such Tim-3 myeloid cells,25 suggesting Finally, carries risk adverse events, given tolerance.10, 13, 18, 19, 21, 23, 24, 26, 28 how uncouple loss self necessary increase efficacy blockade. With (Ipilimumab) (Nivolumab Pembrolizumab) immunotherapy, currently trials, targeting continue grow imminent future. was supported R01 AI40614 P01 AI56299 grants National Institutes Health Evergrande Center Immunologic Diseases. A. H. S. holds patents receives patent royalties related pathway.

Language: Английский

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Targeting sialic acid–Siglec interactions to reverse immune suppression in cancer

Glycobiology, Journal Year: 2017, Volume and Issue: unknown

Published: Dec. 19, 2017

Changes in sialic acids cancer have been observed for many years. In particular, the increase of sialoglycan density or hypersialylation tumors has described. Recent studies identified mechanisms immune evasion based on interactions with immunoregulatory Siglec receptors that are exploited by tumor cells and microorganisms alike. Siglecs mostly inhibitory similar to known checkpoints including PD-1 CTLA-4 successfully targeted blocking antibodies immunotherapy. Here, we summarize changes role play immunity. We also focus potential ways target these sialoglycans order improve anti-cancer

Language: Английский

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Inhibition of the CCL2 receptor, CCR2, enhances tumor response to immune checkpoint therapy

Communications Biology, Journal Year: 2020, Volume and Issue: 3(1)

Published: Nov. 27, 2020

Abstract Immunotherapies targeting the PD-1/PD-L1 axis are now a mainstay in clinical management of multiple cancer types, however, many tumors still fail to respond. CCL2 is highly expressed various types and has been shown be associated with poor prognosis. Inhibition or blockade CCL2/CCR2 signaling thus an area interest for therapy. Here we show across murine tumor metastasis models that CCR2 antagonism combination anti-PD-1 therapy leads sensitization enhanced response over monotherapy. We treatment correlates CD8 + T cell recruitment activation concomitant decrease CD4 regulatory cell. These results provide strong preclinical rationale further exploration combining PD-1/PD-L1-directed immunotherapies especially given availability small molecule inhibitors antibodies.

Language: Английский

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Targeting Aberrant Sialylation to Treat Cancer

Medicines, Journal Year: 2019, Volume and Issue: 6(4), P. 102 - 102

Published: Oct. 13, 2019

Cell surface carbohydrates (known as glycans) are often aberrantly expressed or found at atypical levels in cancer. Glycans can impact all steps tumour progression, from malignant transformation to metastasis, and have roles the cancer hallmarks. An increased understanding of glycans metastatic cascade offers exciting new therapeutic opportunities. Glycan-based targeting strategies currently being tested clinical trials a rich untapped frontier for development. As we learn more about glycobiology, targets will continue emerge drug design. One key change glycosylation is upregulation cancer-associated sialylated glycans. Abnormal sialylation integral growth, metastasis immune evasion; therefore, sialic acid moieties could be high value. Here, summarise changes biology discuss recent advances technologies bringing sialic-acid treatments forefront therapeutics.

Language: Английский

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Colorectal Cancer-Associated Immune Exhaustion Involves T and B Lymphocytes and Conventional NK Cells and Correlates With a Shorter Overall Survival

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 12

Published: Dec. 16, 2021

Colorectal cancer (CRC) is one of the most common worldwide, with a growing impact on public health and clinical management. Immunotherapy has shown promise in treatment advanced cancers, but needs to be improved for CRC, since only limited fraction patients eligible treatment, them develop resistance due progressive immune exhaustion. Here, we identify transcriptional, molecular, cellular traits exhaustion associated CRC determine their relationships patient’s clinic-pathological profile. Bioinformatic analyses RNA-sequencing data 594 CRCs from TCGA PanCancer collection, revealed that, wide range genes, those coding PD-L1 , LAG3 T-bet were (Cramér’s V=0.3) MSI/dMMR tumors shorter overall survival (log-rank test: p= 0.0004, p =0.0014 =0.0043, respectively), whereas high levels expression EOMES TRAF1 FCRL4, BTLA SIGLEC6 =0.0003, =0.0188, =0.0004, =0.0303, =0.0052 =0.0033, independently molecular subtype CRC. Expression PD-L1, PD-1, LAG3, EOMES, TIGIT significantly correlated each other genes CD4 + CD8 CD3 T cell markers NKp46 CD94 markers, (OR >1.5, <0.05), which subset group 1 innate lymphoid cells, namely conventional (c)NK cells. co-occurred both CD3γ, CD3δ, CD3ε, B CD19, CD20 CD79a >2, <0.05). TGFβ1 was CD3ε (odds ratio PD-L2 IDO1 <0.05) cNK SIGLEC2 >2.5; CD19 markers. Morphometric examination immunostained tissue sections, obtained validation cohort 53 patients, substantiated biostatistical findings, showing that highest percentage gene expressing cells found short-term survivors functional not confined lymphocytes, also involves This concept strengthened by CYBERSORTx analysis, additional particular FOXP1, SIRT1, BATF, NR4A1 TOX subpopulations T, NK study provides novel insight into landscape emphasizes need customized multi-targeted therapeutic approach overcome current immunotherapy.

Language: Английский

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The prognostic impact of SIGLEC5-induced impairment of CD8+ T cell activation in sepsis

EBioMedicine, Journal Year: 2023, Volume and Issue: 97, P. 104841 - 104841

Published: Oct. 25, 2023

Sepsis is associated with T-cell exhaustion, which significantly reduces patient outcomes. Therefore, targeting of immune checkpoints (ICs) deemed necessary for effective sepsis management. Here, we evaluated the role SIGLEC5 as an IC ligand and explored its potential a biomarker sepsis.In vitro in vivo assays were conducted to both analyse SIGLEC5's ligand, well assess impact on survival sepsis. A multicentre prospective cohort study was evaluate plasmatic soluble (sSIGLEC5) mortality predictor first 60 days after admission patients. Recruitment included patients (n = 346), controls systemic inflammatory response syndrome 80), aneurism 11), stroke 16), healthy volunteers (HVs, n 100).SIGLEC5 expression monocytes increased by HIF1α higher septic than ex LPS challenge. Furthermore, SIGLEC5-PSGL1 interaction inhibited CD8+ proliferation. Administration sSIGLEC5r (0.8 mg/kg) had adverse effects mouse endotoxemia models. Additionally, plasma sSIGLEC5 levels HVs ROC analysis revealed it marker AUC 0.713 (95% CI, 0.656-0.769; p < 0.0001). Kaplan-Meier curve showed significant decrease above calculated cut-off (HR 3.418, 95% 2.380-4.907, 0.0001 log-rank test) estimated Youden Index (523.6 ng/mL).SIGLEC5 displays hallmarks have been linked patients.Instituto de Salud Carlos III (ISCIII) "Fondos FEDER" ELC (PIE15/00065, PI18/00148, PI14/01234, PI21/00869), CDF (PI21/01178), RLR (FI19/00334) JAO (CD21/00059).

Language: Английский

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The Complex Interaction between the Tumor Micro-Environment and Immune Checkpoints in Breast Cancer

Cancers, Journal Year: 2019, Volume and Issue: 11(8), P. 1205 - 1205

Published: Aug. 19, 2019

The progression of breast cancer and its association with clinical outcome treatment remain largely unexplored. Accumulating data has highlighted the interaction between cells immune system tumor microenvironment in progression, although studies have identified multiple facets within development (TME) constituents, there is lack research into associations subtype staging. Current literature provided insight pathways associated through expression analysis. However, co-expression TME that form pro-tumorigenic relationships contributing to immune-evasion. We focus on checkpoint elements influence particularly molecular subtypes cancer.

Language: Английский

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Immune-related prognosis biomarkers associated with osteosarcoma microenvironment

Cancer Cell International, Journal Year: 2020, Volume and Issue: 20(1)

Published: March 16, 2020

Osteosarcoma is a highly aggressive bone tumor that most commonly affects children and adolescents. Treatment outcomes for osteosarcoma have remained unchanged over the past 30 years. The relationship between immune microenvironment may represent key to its undoing.We calculated stromal scores of cases from Target database using ESTIMATE algorithm. Then we used CIBERSORT algorithm explore analyze infiltration osteosarcoma. Differentially expressed genes (DEGs) were identified based on scores. Search Tool Retrieval Interacting Genes Database (STRING) was utilized assess protein-protein interaction (PPI) information, Molecular Complex Detection (MCODE) plugin screen hub modules PPI network in Cytoscape. prognostic value gene signature validated an independent GSE39058 cohort. Gene set enrichment analysis (GSEA) performed study signaling pathways.From 83 samples obtained dataset, 137 DEGs identified, including 134 upregulated three downregulated genes. Functional networks demonstrated these mainly involved neutrophil degranulation activation response, participated neuroactive ligand-receptor staphylococcus aureus infection.Our established immune-related predict osteosarcoma, which be important targets individual treatment.

Language: Английский

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