Non‐natural MUC1 Glycopeptide Homogeneous Cancer Vaccine with Enhanced Immunogenicity and Therapeutic Activity DOI Creative Commons
Ana Guerreiro, Ismael Compañón, Foivos S. Lazaris

et al.

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(49)

Published: Sept. 14, 2024

Abstract Glycopeptides derived from the glycoprotein mucin‐1 (MUC1) have shown potential as tumor‐associated antigens for cancer vaccine development. However, their low immunogenicity and non‐selective conjugation to carriers present significant challenges clinical efficacy of MUC1‐based vaccines. Here, we introduce a novel candidate based on structure‐guided design an artificial antigen MUC1 glycopeptide. This engineered contains two non‐natural amino acids has α‐ S ‐glycosidic bond, where sulfur replaces conventional oxygen atom linking peptide backbone sugar N ‐acetylgalactosamine. The glycopeptide is then specifically conjugated immunogenic protein carrier CRM 197 (Cross‐Reactive Material 197), approved human use. Conjugation involves selective reduction re‐bridging disulfide in , allowing attachment single copy MUC1. strategy results chemically defined while maintaining both structural integrity carrier. elicits robust Th1‐like immune response mice generates antibodies capable recognizing cells expressing When tested mouse models colon adenocarcinoma pancreatic cancer, effective prophylactic therapeutic use, significantly delaying tumor growth. In applications, improved outcomes were observed when was combined with anti‐programmed cell death 1 (anti‐PD‐1) checkpoint inhibitor. Our reduces batch‐to‐batch variability enhances potential. site‐specific approach disputes prevailing dogma glycoconjugate vaccines require multivalent display antigens.

Language: Английский

Disruption of the sialic acid/Siglec-9 axis improves antibody-mediated neutrophil cytotoxicity towards tumor cells DOI Creative Commons
Marta Lustig, Chilam Chan,

J.H. Marco Jansen

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: June 6, 2023

Upregulation of surface expressed sialoglycans on tumor cells is one the mechanisms which promote growth and progression. Specifically, interactions sialic acids with acid-binding immunoglobulin-like lectins (Siglecs) lymphoid or myeloid transmit inhibitory signals lead to suppression anti-tumor responses. Here, we show that neutrophils express among others Siglec-9, EGFR HER2 positive breast ligands for Siglec-9. Treatment neuraminidases a sialyl transferase inhibitor significantly reduced binding soluble recombinant Siglec-9-Fc fusion protein, while expression remained unchanged. Importantly, cytotoxic activity driven by therapeutic antibodies in vitro was increased blocking acid/Siglec interaction, either reducing cell sialylation Siglec-9 antibody containing an effector silenced Fc domain. In vivo short-term xenograft mouse model confirmed improved efficacy against acid depleted, sialyltransferase inhibitor, compared untreated cells. Our studies demonstrate between can impair dependent killing, polymorphonuclear (PMN) critically involved. Considering PMN are often highly abundant population microenvironment, constitutes promising target checkpoint blockade improve antibody-based immunotherapy.

Language: Английский

Citations

21
Unraveling the impact of sialic acids on the immune landscape and immunotherapy efficacy in pancreatic cancer DOI Creative Commons
Kelly Boelaars,

Laura Goossens-Kruijssen,

Di Wang

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2023, Volume and Issue: 11(11), P. e007805 - e007805

Published: Nov. 1, 2023

Background Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Despite successful application immune checkpoint blockade in a range human cancers, immunotherapy PDAC remains unsuccessful. characterized by desmoplastic, hypoxic and highly immunosuppressive tumor microenvironment (TME), where T-cell infiltration often lacking (immune desert), or T cells are located distant from islands excluded). Converting TME to an immune-inflamed state, allowing infiltration, could increase success PDAC. Method In this study, we use KPC3 subcutaneous mouse model investigate role tumor-derived sialic acids shaping landscape. A acid deficient line was generated genetic knock-out CMAS (cytidine monophosphate N-acetylneuraminic synthetase) enzyme, critical enzyme synthesis acid-containing glycans. The effect acid-deficiency on efficacy assessed treatment with anti-programmed cell death protein 1 (PD-1) agonistic CD40. Result absence tumors resulted increased numbers CD4 + CD8 TME, reduced frequencies regulatory (Tregs) within population. Importantly, were able infiltrate acid-deficient tumors. These favorable alterations landscape sensitized immunotherapy, which ineffective acid-expressing addition, high expression sialylation-related genes pancreatic cancer correlated decreased presence Tregs, poorer survival probability. Conclusion Our results demonstrate that mediate exclusion thereby impairing efficacy. Targeting represents potential strategy enhance improve outcomes

Language: Английский

Citations

20
Targeting myeloid cells for cancer immunotherapy: Siglec-7/9/10/15 and their ligands DOI Creative Commons
Kelly Boelaars, Yvette van Kooyk

Trends in cancer, Journal Year: 2023, Volume and Issue: 10(3), P. 230 - 241

Published: Dec. 29, 2023

Advances in immunotherapy have revolutionized cancer treatment, yet many patients do not show clinical responses. While most immunotherapies target T cells, myeloid cells are the abundant cell type solid tumors and key orchestrators of immunosuppressive tumor microenvironment (TME), hampering effective Therefore, unraveling immune suppressive pathways within could unveil new avenues for immunotherapy. Over past decade, Siglec receptors their ligand, sialic acids, emerged as a novel checkpoint on cells. In this review, we highlight findings how acids modify immunity TME through engagement Siglec-7/9/10/15 expressed acid–Siglec axis can be targeted future immunotherapies.

Language: Английский

Citations

17
Siglec9 + tumor-associated macrophages predict prognosis and therapeutic vulnerability in patients with colon cancer DOI Creative Commons
Chang Jiang, Qingyang Feng, Yihao Mao

et al.

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 130, P. 111771 - 111771

Published: March 1, 2024

Siglec9 has been identified as an immune checkpoint molecule on tumor-associated macrophages (TAMs). Nevertheless, the expression profile and clinical significance of + TAMs in colon cancer (CC) are still not fully understood. Two cohorts from distinct medical centers were retrospectively enrolled. Immunohistochemistry immunofluorescence conducted to evaluate infiltration cells. Single-cell RNA sequencing flow cytometry utilized identify impact tumor environment, which was subsequently validated through bioinformatics analysis TCGA database. Prognosis benefit adjuvant chemotherapy (ACT) also evaluated using Cox regression Kaplan-Meier method. High associated with worse prognosis better 6-month ACT. contributed immunoevasion by promoting immunosuppressive cells dysfunction process CD8 T Additionally, high mesenchymal-featured subtype overexpression VEGF signaling pathway, strongest communication between vascular endothelial may serve a biomarker for response ACT CC. Furthermore, immunoevasive contexture angiogenesis stimulated suggest potential treatment combinations CC patients.

Language: Английский

Citations

8
Siglec-15 on macrophages suppress the immune microenvironment in patients with PD-L1 negative non-metastasis lung adenocarcinoma DOI Creative Commons
Ziqi Huang, Yan Guo, Baihui Li

et al.

Cancer Gene Therapy, Journal Year: 2023, Volume and Issue: 31(3), P. 427 - 438

Published: Dec. 11, 2023

Abstract Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is an immune checkpoint molecule with sequence homology to programmed cell death ligand 1 (PD-L1), which mainly expressed on macrophages and tumor cells. However, whether Siglec-15-induced immunosuppression poor prognosis are independent of PD-L1 remains unclear. In this study, we collected samples 135 non-small lung cancers found that Siglec-15 expression were in cancer by multiple immunofluorescence staining. (Mφ-Siglec-15) was significantly associated DFS ( p < 0.05) − patients non-metastasis adenocarcinoma, not + or squamous carcinoma patients. Moreover, stromal Mφ-Siglec-15 more than those = 0.002). We further polarized toward M2 produced IL-10, negatively inflamed immunophenotype may inhibit CD8 T cells infiltration. conclusion, PD-L1-independent contribute the formation immunosuppressive microenvironment adenocarcinoma patients, cause a higher risk recurrence. could be potential target for normalizing immunotherapy, benefiting who fail respond anti-PD-L1 therapy.

Language: Английский

Citations

15
Glycosylation Targeting: A Paradigm Shift in Cancer Immunotherapy DOI Creative Commons
Xueting Ren,

Shuai Lin,

Feng Guan

et al.

International Journal of Biological Sciences, Journal Year: 2024, Volume and Issue: 20(7), P. 2607 - 2621

Published: Jan. 1, 2024

Immunotherapy has shown great potential in cancer treatment.However, even with the intervention of techniques such as immune checkpoint inhibitor therapy, tumors can still achieve escape, leading to a low response rate.Abnormal glycosylation is widely recognized hallmark cancer.The development complex "glyco-code" on surface tumor cells potentially influence system's ability monitor and impact anti-tumor response.Therefore, abnormal emerged promising target for immunotherapy.Many recent studies have that targeted reshape microenvironment (TME) promote response, thereby improving immunotherapy.This review summarizes how affects function TME synthesizes latest research progress immunotherapy.It hoped by elucidating basic laws biological connotations glycosylation, this will enable researcher thoroughly analyze mechanism its metabolic regulation network, which provide theoretical tool promoting clinical application codes.

Language: Английский

Citations

6
Unraveling Molecular Recognition of Glycan Ligands by Siglec-9 via NMR Spectroscopy and Molecular Dynamics Modeling DOI Creative Commons
Unai Atxabal, Corwin M. Nycholat,

Johannes M. Pröpster

et al.

ACS Chemical Biology, Journal Year: 2024, Volume and Issue: 19(2), P. 483 - 496

Published: Feb. 7, 2024

Human sialic-acid-binding immunoglobulin-like lectin-9 (Siglec-9) is a glycoimmune checkpoint receptor expressed on several immune cells. Binding of Siglec-9 to sialic acid containing glycans (sialoglycans) well documented modulate its functions as an inhibitory receptor. Here, we first assigned the amino backbone V-set domain (Siglec-9

Language: Английский

Citations

5
Targeting Siglec–Sialylated MUC1 Immune Axis in Cancer DOI Open Access
Ramya Ayyalasomayajula, Mare Čudić

Cancers, Journal Year: 2024, Volume and Issue: 16(7), P. 1334 - 1334

Published: March 29, 2024

Siglecs play a key role in mediating cell–cell interactions via the recognition of different sialylated glycoconjugates, including tumor-associated MUC1, which can lead to activation or inhibition immune response. The occurs through signaling with cytoplasmic immunoreceptor tyrosine-based motif (ITAM)-containing proteins, while signal is result interaction intracellular (ITIM)-bearing receptors. MUC1 glycans ITIM motifs decreases antitumor immunity. Consequently, these are expected tumor evasion. Efforts modulate response cells by blocking immune-suppressive effects inhibitory Siglecs, driving immune-activating and/or altering synthesis and expression sialic acid glycocalyx new therapeutic strategies deserving further investigation. We will highlight Siglec’s family receptors evasion glycan ligands their natural context, presented on protein such as factors affecting fine binding specificities, multivalency either at ligand receptor side, spatial organization, finally current future interventions targeting Siglec–sialylated axis cancer.

Language: Английский

Citations

5
Unlocking the Power of Sugar: Carbohydrate Ligands as Key Players in Nanotherapeutic-Assisted Targeted Cancer Therapy DOI
Rajan Swami,

Sahil Vij,

Shubham Sharma

et al.

Nanomedicine, Journal Year: 2024, Volume and Issue: 19(5), P. 431 - 453

Published: Jan. 30, 2024

Cancer cells need as much 40-times more sugar than their normal cell counterparts. This demand is attained by the excessive expression of inimitable transporters on surface cancer cells, driven voracious appetite for carbohydrates. Nanotechnological advances drive research utilizing ligand-directed therapeutics and diverse carbohydrate analogs. The precise delivery these therapeutic cargos not only mitigates toxicity associated with chemotherapy but also reduces grim toll mortality morbidity among patients. in-depth review explores potential ligands in advanced treatment using nanoparticles. It offers a broader perspective beyond usual ways we deliver drugs, potentially changing way fight cancer.

Language: Английский

Citations

4
Siglec-9+tumor-associated macrophages delineate an immunosuppressive subset with therapeutic vulnerability in patients with high-grade serous ovarian cancer DOI Creative Commons

Yiying Wang,

Mengdi He, Chen Zhang

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2023, Volume and Issue: 11(9), P. e007099 - e007099

Published: Sept. 1, 2023

Background The potent immunosuppressive properties of sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) on myeloid cells and lymphocytes provide a strong rationale for serving as therapeutic target. However, the expression profile critical role Siglec-9 in high-grade serous ovarian cancer (HGSC) remain obscure. This study aimed to elucidate prognostic significance its predictive value immunotherapy HGSC. Methods Study enrolled two cohorts, consisting 120 tumor microarray specimens HGSC immunohistochemistry (IHC) 40 fresh flow cytometry (FCM). Expression immune was analyzed by both bioinformatics analysis FCM. Role studied identify that + TAMs linked with an phenotype IHC FCM, block sensitive ex vivo vitro assays. Results is predominantly expressed tumor-associated macrophages (TAMs). High were associated inferior overall survival (OS). Both tumor-conditioned medium (TCM) ascites induced enrichment protumorigenic phenotypes. microenvironment (TME) characterized exhausted CD8 T increased checkpoint expression. Blockade suppressed phosphorylation inhibitory phosphatase SHP-1 repolarized antitumorigenic retrieved cytotoxic activity vivo. Responders toward antiprogrammed death receptor-1 (anti-PD-1) therapy present more than non-responders. Furthermore, blockade synergized anti-PD-1 antibody enhance tissues higher TAMs. Conclusions may serve independent poor but biomarker anti-PD-1/antiprogrammed ligand-1 In addition, potential target worth further exploration.

Language: Английский

Citations

10