Polysialic acid is upregulated on activated immune cells and negatively regulates anticancer immune activity

Olivia Drummond-Guy; John Daly; Angeline Wu; Natalie Stewart; Katy Milne; Chloe Duff; Brad H Nelson; Karla C Williams; Simon Wisnovsky

doi:10.3389/fonc.2025.1520948

Polysialic acid is upregulated on activated immune cells and negatively regulates anticancer immune activity

Front Oncol. 2025 Mar 20:15:1520948. doi: 10.3389/fonc.2025.1520948. eCollection 2025.

Authors

Affiliations

¹ Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
² Deeley Research Centre, British Columbia (BC) Cancer, Victoria, BC, Canada.
³ Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
⁴ Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada.

Abstract

Suppression of anticancer immune function is a key driver of tumorigenesis. Identifying molecular pathways that inhibit anticancer immunity is critical for developing novel immunotherapeutics. One such molecule that has recently been identified is the carbohydrate polysialic acid (polySia), whose expression is dramatically upregulated on both cancer cells and immune cells in breast cancer patient tissues. The role of polySia in the anticancer immune response, however, remains incompletely understood. In this study, we profile polySia expression on both healthy primary immune cells and on infiltrating immune cells in the tumour microenvironment (TME). These studies reveal polySia expression on multiple immune cell subsets in patient breast tumors. We find that stimulation of primary T-cells and macrophages in vitro induces a significant upregulation of polySia expression. We subsequently show that polySia is appended to a range of different carrier proteins within these immune cells. Finally, we find that selective removal of polySia can significantly potentiate killing of breast cancer cells by innate immune cells. These studies implicate polySia as a significant negative regulator of anticancer immunity.

Keywords: B cells; NK cells; T-cells; carbohydrates; glycans; immune cells; macrophages; polysialic acid.

Grants and funding

The author(s) declare that financial support was received for the research and/or publication of this article. S.W. and K.C.W. acknowledge funding from the Canadian Institutes of Health Research, the Cancer Research Society, the Canadian Glycomics Network, and Michael Smith Health Research BC. K.C.W holds a Canada Research Chair, Tier 2, and S.W. holds a Michael Smith Health Research Scholar Award. John Daly acknowledges funding from a Canadian Arthritis Society Postdoctoral Fellowship. Natalie Stewart acknowledges funding from a Cancer Research Society Doctoral Research Award. Angeline Wu acknowledges funding from a National Science and Engineering Research Council of Canada gradiate scholarship (NSERC CGS-M).