首页|A tumor-associated heparan sulfate-related glycosaminoglycan promotes the generation of functional regulatory T cells

A tumor-associated heparan sulfate-related glycosaminoglycan promotes the generation of functional regulatory T cells

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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(Ca1 0H)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.

Tumoral carbohydrate A10Heparan sulfate-related proteoglycanCancer immunologyDendritic cellRegulatory T cell

Leticia Martín-Cruz、Marcos Vi?uela、Ioanna Kalograiaki、Alba Angelina、Paola Oquist-Phillips、Irene Real-Arévalo、Francisco Javier Ca?ada、José Ignacio Tudela、Luis Moltó、Jesús Moreno-Sierra、José Luis Subiza、Oscar Palomares

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Department of Biochemistry and Molecular Biology,School of Chemistry,Complutense University of Madrid,Madrid,Spain

Inmunotek,Alcalá de Henares,Madrid,Spain

Fundación Investigación Hospital Clínico San Carlos,Martin Lagos s/n,28040 Madrid,Spain

Centro de Investigaciones Biológicas Margarita Salas,CSIC,Ramiro de Maetzu 9,28040 Madrid,Spain

CIBER de Enfermedades Respiratorias(CIBERES)Avda,Monforte de Lemos,3-5,28029 Madrid,Spain

Servicio de Urología,Hospital Clínico San Carlos,Universidad Complutense de Madrid,Martín Lagos s/n,28040 Madrid,Spain

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&&&&MINECO(Spain)Ministerio de Ciencia e Innovación(Spain)MCIN/AEI/10.13039/501100011033(Spain)MINECOFPU and UCM predoctoral fellowships

FEI 16_60Art.83 4154605138/201224/2013SAF-2017-84978-RPID2020-114396RB-I00PID2021-123781OB-C22RTC-2015-3805-1

2023

10.1038/s41423-023-01096-9

中国免疫学杂志(英文版)
中国免疫学会

中国免疫学杂志(英文版)

CSTPCDCSCDSCI
影响因子：0.731
ISSN：1672-7681
年,卷(期)：2023.20(12)
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