期刊
EMBO JOURNAL
卷 38, 期 11, 页码 -出版社
WILEY
DOI: 10.15252/embj.2018100012
关键词
HSPG; immunosurveillance; MDSC; NK cells; TRF2
资金
- FEDER
- Ministere de l'Enseignement Superieur
- Region Provence Alpes-Cote d'Azur
- Conseil Departemental 06
- ITMO Cancer Aviesan (plan cancer)
- Canceropole PACA [2016-04]
- Association pour la Recherche sur le Cancer (ARC)
- Infrastructures en Biologie Sante et Agronomie (IBiSA)
- University of Nice Sophia-Antipolis
- l'Inserm
- Fondation ARC pour la recherche sur le cancer [PJA 20151203504, PGA20160203873]
- INCa [2016-04]
- Fondation de France
- Ligue Contre le Cancer (EG Equipe labellisee)
- Investments for the Future LABEX SIGNALIFE [ANR-11-LABX-0028-01]
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (TILC) [694502]
- Agence Nationale de la Recherche
- Equipe Labellisee La Ligue
- Ligue Nationale contre le Cancer
- MSDAvenir
- Innate Pharma
- Italian Association for Cancer Research (AIRC) [16910, 21579]
- Umberto Veronesi Foundation (FUV)
Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with strong immunosuppressive activity that promote tumor growth. In this study, we describe a mechanism by which cancer cells control MDSCs in human cancers by upregulating TRF2, a protein required for telomere stability. Specifically, we showed that the TRF2 upregulation in cancer cells has extratelomeric roles in activating the expression of a network of genes involved in the biosynthesis of heparan sulfate proteoglycan, leading to profound changes in glycocalyx length and stiffness, as revealed by atomic force microscopy. This TRF2-dependent regulation facilitated the recruitment of MDSCs, their activation via the TLR2/MyD88/IL-6/STAT3 pathway leading to the inhibition of natural killer recruitment and cytotoxicity, and ultimately tumor progression and metastasis. The clinical relevance of these findings is supported by our analysis of cancer cohorts, which showed a correlation between high TRF2 expression and MDSC infiltration, which was inversely correlated with overall patient survival.
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