Sialic acids in pancreatic cancer cells drive tumour-associated macrophage differentiation via the Siglec receptors Siglec-7 and Siglec-9.
| Title: | Sialic acids in pancreatic cancer cells drive tumour-associated macrophage differentiation via the Siglec receptors Siglec-7 and Siglec-9. |
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| Authors: | Rodriguez E; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands.; Boelaars K; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands.; Brown K; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands.; Eveline Li RJ; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands.; Kruijssen L; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands.; Bruijns SCM; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands.; van Ee T; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands.; Schetters STT; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands.; Crommentuijn MHW; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands.; van der Horst JC; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands.; van Grieken NCT; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Pathology, Amsterdam, Netherlands.; van Vliet SJ; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands.; Kazemier G; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Surgery, Cancer Center Amsterdam, Amsterdam, Netherlands.; Giovannetti E; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands.; Cancer Pharmacology Lab, AIRC Start-Up Unit, Fondazione Pisana per la Scienza, Pisa, Italy.; Garcia-Vallejo JJ; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands.; van Kooyk Y; Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands. y.vankooyk@amsterdamumc.nl. |
| Source: | Nature communications [Nat Commun] 2021 Feb 24; Vol. 12 (1), pp. 1270. Date of Electronic Publication: 2021 Feb 24. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [London] : Nature Pub. Group |
| MeSH Terms: | Antigens, CD/*metabolism ; Antigens, Differentiation, Myelomonocytic/*metabolism ; Lectins/*metabolism ; Macrophages/*cytology ; Macrophages/*metabolism ; Monocytes/*cytology ; Monocytes/*metabolism ; Pancreas/*metabolism ; Pancreatic Neoplasms/*metabolism ; Sialic Acid Binding Immunoglobulin-like Lectins/*metabolism ; Sialic Acids/*pharmacology; Antigens, CD/genetics ; Antigens, Differentiation, Myelomonocytic/genetics ; Cell Differentiation/drug effects ; Clustered Regularly Interspaced Short Palindromic Repeats/genetics ; Lectins/genetics ; Macrophages/drug effects ; Monocytes/drug effects ; Phosphorylation/drug effects ; Sialic Acid Binding Immunoglobulin-like Lectins/genetics ; Cell Line, Tumor ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Humans |
| Abstract: | Changes in glycosylation during tumour progression are a key hallmark of cancer. One of the glycan moieties generally overexpressed in cancer are sialic acids, which can induce immunomodulatory properties via binding to Siglec receptors. We here show that Pancreatic Ductal Adenocarcinoma (PDAC) tumour cells present an increased sialylation that can be recognized by Siglec-7 and Siglec-9 on myeloid cells. We identified the expression of the α2,3 sialyltransferases ST3GAL1 and ST3GAL4 as main contributor to the synthesis of ligands for Siglec-7 and Siglec-9 in tumour cells. Analysing the myeloid composition in PDAC, using single cell and bulk transcriptomics data, we identified monocyte-derived macrophages as contributors to the poor clinical outcome. Tumour-derived sialic acids dictate monocyte to macrophage differentiation via signalling through Siglec-7 and Siglec-9. Moreover, triggering of Siglec-9 in macrophages reduce inflammatory programmes, while increasing PD-L1 and IL-10 expression, illustrating that sialic acids modulate different myeloid cells. This work highlights a critical role for sialylated glycans in controlling immune suppression and provides new potential targets for cancer immunotherapy in PDAC. |
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| Substance Nomenclature: | 0 (Antigens, CD); 0 (Antigens, Differentiation, Myelomonocytic); 0 (Lectins); 0 (SIGLEC7 protein, human); 0 (SIGLEC9 protein, human); 0 (Sialic Acid Binding Immunoglobulin-like Lectins); 0 (Sialic Acids) |
| Entry Date(s): | Date Created: 20210225 Date Completed: 20210303 Latest Revision: 20240102 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC7904912 |
| DOI: | 10.1038/s41467-021-21550-4 |
| PMID: | 33627655 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't