CD44-CD206 axis drives dendritic cell loss and immunosuppression in immaturely glycosylated bladder tumours
Year: 2026
Type: preprint
Abstract: Antigen-presenting-cell dysfunction drives immune exclusion, but how tumour glycans disable these cells remains incompletely defined. Immature O -glycosylation, marked by Tn and sialyl-Tn antigens, drives myeloid dysfunction in bladder cancer. Transcriptomics and human tumour profiling linked this state to reduced representation of antigen-presenting myeloid cells and attenuated lymphoid-effector programmes. In glycoengineered models, immature O -glycans promoted immunoregulatory macrophage phenotypes and contact-dependent death of monocyte-derived dendritic cells (moDCs), while surviving cells showed impaired maturation and T-cell activation. Tumour-cell CD44 standard isoform was required for DC death, which was accompanied by inflammasome-associated proteins and gasdermin D cleavage, consistent with pyroptosis. Receptor-discovery approaches converged on CD206, which bound immaturely glycosylated CD44. CD206 blockade restored DC viability. In immunocompetent mice, immature glycosylation accelerated tumour growth and depleted conventional DCs, whereas CD206 blockade restrained tumour progression and restored local and nodal myeloid and lymphoid immunity. These findings identify CD44-CD206 as a targetable glycoimmune checkpoint that promotes immune exclusion.
Authors: Andreia Miranda, Dylan Ferreira, Rui Freitas, Andreia Peixoto, Andreia Brandão, Michael de Kok, Eduardo Ferreira, Marta Relvas-Santos, Camila Lourenço, Magali Grange, Flávia Castro, Luís Pedro Afonso, Carlos Palmeira, Lúcio Lara Santos, Maria José Oliveira, Hervé Luche, Yvette van Kooyk, José Alexandre Ferreira
Institutions: Universidade do Porto, IPO Porto, Amsterdam University Medical Centers, i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Instituto de Ciências Biomédicas Albel Salazar, Vrije Universiteit Amsterdam, Amsterdam UMC Location Vrije Universiteit Amsterdam, Fernando Pessoa University, Centre National de la Recherche Scientifique, Inserm, Aix-Marseille Université, Centre d'Immunophénomique
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7224095953