RT Journal Article
T1 A tumor-associated heparan sulfate-related glycosaminoglycan promotes the generation of functional regulatory T cells
A1 Martín De La Cruz, Leticia
A1 Viñuela, Marcos
A1 Kalograiaki, Ioanna
A1 Angelina Querencias, Alba
A1 Oquist Phillips, Mayra Paola
A1 Real-Arévalo, Irene
A1 Cañada, Francisco Javier
A1 Tudela, José Ignacio
A1 Moltó, Luis
A1 Moreno Sierra, Jesús
A1 Subiza, José Luis
A1 Palomares Gracia, Óscar
AB Functional Tregs play a key role in tumor development and progression, representing a major barrier to anticancer immunity. The mechanisms by which Tregs are generated in cancer and the influence of the tumor microenvironment on these processes remain incompletely understood. Herein, by using NMR, chemoenzymatic structural assays and a plethora of in vitro and in vivo functional analyses, we demonstrate that the tumoral carbohydrate A10 (Ca10), a cell-surface carbohydrate derived from Ehrlich’s tumor (ET) cells, is a heparan sulfate-related proteoglycan that enhances glycolysis and promotes the development of tolerogenic features in human DCs. Ca10-stimulated human DCs generate highly suppressive Tregs by mechanisms partially dependent on metabolic reprogramming, PD-L1, IL-10, and IDO. Ca10 also reprograms the differentiation of human monocytes into DCs with tolerogenic features. In solid ET-bearing mice, we found positive correlations between Ca10 serum levels, tumor size and splenic Treg numbers. Administration of isolated Ca10 also increases the proportion of splenic Tregs in tumor-free mice. Remarkably, we provide evidence supporting the presence of a circulating human Ca10 counterpart (Ca10H) and show, for the first time, that serum levels of Ca10H are increased in patients suffering from different cancer types compared to healthy individuals. Of note, these levels are higher in prostate cancer patients with bone metastases than in prostate cancer patients without metastases. Collectively, we reveal novel molecular mechanisms by which heparan sulfate-related structures associated with tumor cells promote the generation of functional Tregs in cancer. The discovery of this novel structural-functional relationship may open new avenues of research with important clinical implications in cancer treatment.
PB Springer Nature
SN 2042-0226
YR 2023
FD 2023
LK https://hdl.handle.net/20.500.14352/95323
UL https://hdl.handle.net/20.500.14352/95323
LA eng
NO Martín-Cruz, L., Viñuela, M., Kalograiaki, I. et al. A tumor-associated heparan sulfate-related glycosaminoglycan promotes the generation of functional regulatory T cells. Cell Mol Immunol 20, 1499–1512 (2023). https://doi.org/10.1038/s41423-023-01096-9
NO Ministerio de Economía y Competitividad (España)
NO Ministerio de Ciencia e Innovación (España)
DS Docta Complutense
RD 16 abr 2025