The glycosyltransferase ST3GAL4 drives immune evasion in acute myeloid leukemia by synthesizing ligands for the glyco-immune checkpoint receptor Siglec-9.

Autor: Krishnamoorthy V; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada., Daly J; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada., Kim J; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada., Piatnitca L; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada., Yuen KA; Terry Fox Laboratory, British Columbia Cancer Research Institute, Vancouver, BC, Canada., Kumar B; Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA., Taherzadeh Ghahfarrokhi M; Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA., Bui TQT; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.; Terry Fox Laboratory, British Columbia Cancer Research Institute, Vancouver, BC, Canada., Azadi P; Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA., Vu LP; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.; Terry Fox Laboratory, British Columbia Cancer Research Institute, Vancouver, BC, Canada., Wisnovsky S; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada. simon.wisnovsky@ubc.ca.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2024 Nov 17. Date of Electronic Publication: 2024 Nov 17.
DOI: 10.1038/s41375-024-02454-w
Abstrakt: Immunotherapy has demonstrated promise as a treatment for acute myeloid leukemia (AML). However, there is still an urgent need to identify new molecules that inhibit the immune response to AML. Most prior research in this area has focused on protein-protein interaction interfaces. While carbohydrates also regulate immune recognition, the role of cell-surface glycans in driving AML immune evasion is comparatively understudied. The Siglecs, for example, are an important family of inhibitory, glycan-binding signaling receptors that have emerged as prime targets for cancer immunotherapy in recent years. In this study, we find that AML cells express ligands for the receptor Siglec-9 at high levels. Integrated CRISPR genomic screening and clinical bioinformatic analysis identified ST3GAL4 as a potential driver of Siglec-9 ligand expression in AML. Depletion of ST3GAL4 by CRISPR-Cas9 knockout (KO) dramatically reduced the expression of Siglec-9 ligands in AML cells. Mass spectrometry analysis of cell-surface glycosylation in ST3GAL4 KO cells revealed that Siglec-9 primarily binds N-linked sialoglycans on these cell types. Finally, we found that ST3GAL4 KO enhanced the sensitivity of AML cells to phagocytosis by Siglec-9-expressing macrophages. This work reveals a novel axis of immune evasion and implicates ST3GAL4 as a possible target for  immunotherapy in AML.
Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate Primary AML bone marrow and peripheral blood samples were obtained from the hematology cell bank at BC Cancer Research Centre in a manner complying with all relevant guidelines. The study complies with ethical regulations as approved by the University of British Columbia Human Ethics Board (H24-01726). Informed consent was obtained from all subjects.
(© 2024. The Author(s).)
Databáze: MEDLINE
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