CD44-CD206 axis drives dendritic cell loss and immunosuppression in immaturely glycosylated bladder tumours
- 1Portuguese Institute of Oncology of Porto
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.
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BibTeX
@misc{miranda2026cd44cd206,
title = {{CD44-CD206 axis drives dendritic cell loss and immunosuppression in immaturely glycosylated bladder tumours}},
author = {A. Miranda and D. Ferreira and R. Freitas and A. Peixoto and A. Brandao and M. de Kok and E. Ferreira and M. Relvas-Santos and C. Lourenco and M. Grange and F. Castro and L. P. Afonso and C. Palmeira and L. L. Santos and M. J. Oliveira and H. Luche and Y. van Kooyk and J. A. Ferreira},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.25.761623},
url = {https://www.biorxiv.org/content/10.64898/2026.10.25.761623v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - CD44-CD206 axis drives dendritic cell loss and immunosuppression in immaturely glycosylated bladder tumours
AU - A. Miranda
AU - D. Ferreira
AU - R. Freitas
AU - A. Peixoto
AU - A. Brandao
AU - M. de Kok
AU - E. Ferreira
AU - M. Relvas-Santos
AU - C. Lourenco
AU - M. Grange
AU - F. Castro
AU - L. P. Afonso
AU - C. Palmeira
AU - L. L. Santos
AU - M. J. Oliveira
AU - H. Luche
AU - Y. van Kooyk
AU - J. A. Ferreira
PY - 2026
DA - 2026/10/25
PB - bioRxiv
DO - 10.64898/2026.10.25.761623
UR - https://www.biorxiv.org/content/10.64898/2026.10.25.761623v1
AB - 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.
ER -