Pancreatic cancer-associated fibroblasts modulate macrophage differentiation via sialic acid-Siglec interactions

Boelaars, Kelly, Rodriguez, Ernesto, Huinen, Zowi R, Liu, Chang, Wang, Di, Springer, Babet O, Olesek, Katarzyna, Goossens-Kruijssen, Laura, van Ee, Thomas, Lindijer, Dimitri, Tak, Willemijn, de Haas, Aram, Wehry, Laetitia, Nugteren-Boogaard, Joline P, Mikula, Aleksandra, de Winde, Charlotte M, Mebius, Reina E, Tuveson, David A, Giovannetti, Elisa, Bijlsma, Maarten F, Wuhrer, Manfred, van Vliet, Sandra J, van Kooyk, Yvette (April 2024) Pancreatic cancer-associated fibroblasts modulate macrophage differentiation via sialic acid-Siglec interactions. Communications Biology, 7 (1). p. 430. ISSN 2399-3642 (Public Dataset)

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Abstract

Despite recent advances in cancer immunotherapy, pancreatic ductal adenocarcinoma (PDAC) remains unresponsive due to an immunosuppressive tumor microenvironment, which is characterized by the abundance of cancer-associated fibroblasts (CAFs). Once identified, CAF-mediated immune inhibitory mechanisms could be exploited for cancer immunotherapy. Siglec receptors are increasingly recognized as immune checkpoints, and their ligands, sialic acids, are known to be overexpressed by cancer cells. Here, we unveil a previously unrecognized role of sialic acid-containing glycans on PDAC CAFs as crucial modulators of myeloid cells. Using multiplex immunohistochemistry and transcriptomics, we show that PDAC stroma is enriched in sialic acid-containing glycans compared to tumor cells and normal fibroblasts, and characterized by ST3GAL4 expression. We demonstrate that sialic acids on CAF cell lines serve as ligands for Siglec-7, -9, -10 and -15, distinct from the ligands on tumor cells, and that these receptors are found on myeloid cells in the stroma of PDAC biopsies. Furthermore, we show that CAFs drive the differentiation of monocytes to immunosuppressive tumor-associated macrophages in vitro, and that CAF sialylation plays a dominant role in this process compared to tumor cell sialylation. Collectively, our findings unravel sialic acids as a mechanism of CAF-mediated immunomodulation, which may provide targets for immunotherapy in PDAC.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types > fibroblasts organs, tissues, organelles, cell types and functions > cell types and functions > cell types > fibroblasts organs, tissues, organelles, cell types and functions > cell types and functions > cell types > fibroblasts organs, tissues, organelles, cell types and functions diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > cancer types
CSHL Authors:	Tuveson, David A.
Communities:	CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL labs > Tuveson lab CSHL Cancer Center Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	9 April 2024
Date Deposited:	11 Apr 2024 12:47
Last Modified:	11 Apr 2024 12:47
PMCID:	PMC11003967
Related URLs:	Publisher
Dataset ID:	GSA: PRJCA001063 https://github.com/MolecularCellBiologyImmunology/Sialylation_ CAF GEO: GSE933264
URI:	https://repository.cshl.edu/id/eprint/41489

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