CD44-CD206 axis drives dendritic cell loss and immunosuppression in immaturely glycosylated bladder tumours
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
- Flávia Castro (ORCID: https://orcid.org/0000-0002-2273-2806)
- Magali Grange (ORCID: https://orcid.org/0009-0006-1720-794X)
- Lúcio Lara Santos (ORCID: https://orcid.org/0000-0002-0521-5655)
- Yvette van Kooyk (ORCID: https://orcid.org/0000-0001-5997-3665)
- Carlos Palmeira (ORCID: https://orcid.org/0000-0002-4833-2202)
- María José Oliveira (ORCID: https://orcid.org/0000-0002-0724-0272)
- Andreia Peixoto (ORCID: https://orcid.org/0000-0001-9514-0775)
- Marta Relvas‐Santos (ORCID: https://orcid.org/0000-0001-5764-5414)
- Dylan Ferreira (ORCID: https://orcid.org/0000-0001-9224-0121)
- Rui Freitas (ORCID: https://orcid.org/0000-0003-0723-8719)
- José Alexandre Ferreira (ORCID: https://orcid.org/0000-0002-0097-6148)
- Andréia Miranda (ORCID: https://orcid.org/0000-0002-5441-4888)
- Hervé Luche (ORCID: https://orcid.org/0000-0003-4309-8338)
- Michael de Kok (ORCID: https://orcid.org/0000-0001-6652-2723)
- Luís Pedro Afonso (ORCID: https://orcid.org/0000-0002-6354-7332)
- Eduardo Ferreira (ORCID: https://orcid.org/0009-0003-3258-8451)
- Andreia Brandão (ORCID: https://orcid.org/0000-0003-0938-1543)
- Camila Lourenco
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Universidade do Porto (PT)
- Aix-Marseille Université (FR)
- IPO Porto (PT)
- Centre d’Immunologie de Marseille-Luminy (FR)
- Amsterdam University Medical Centers (NL)
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto (PT)
- Centre d'Immunophénomique (FR)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-10-28
- DOI
- https://doi.org/10.64898/2026.10.25.761623
- Primary Topic
- Immunotherapy and Immune Responses
- Type
- preprint