TIE-2 Signaling Activation by Angiopoietin 2 On Myeloid-Derived Suppressor Cells Promotes Melanoma-Specific T-cell Inhibition.
Fiche publication
Date publication
juillet 2022
Journal
Frontiers in immunology
Auteurs
Membres identifiés du Cancéropôle Est :
Pr ADOTEVI Olivier, Pr AUBIN François, Mme LAHEURTE Caroline, Dr NARDIN Charlée
Tous les auteurs :
Marguier A, Laheurte C, Lecoester B, Malfroy M, Boullerot L, Renaudin A, Seffar E, Kumar A, Nardin C, Aubin F, Adotevi O
Lien Pubmed
Résumé
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immune suppressive cells detected in several human cancers. In this study, we investigated the features and immune suppressive function of a novel subset of monocytic MDSC overexpressing TIE-2 (TIE-2 M-MDSC), the receptor for the pro-angiogenic factor angiopoietin 2 (ANGPT2). We showed that patients with melanoma exhibited a higher circulating rate of TIE-2 M-MDSCs, especially in advanced stages, as compared to healthy donors. The distribution of the TIE-2 M-MDSC rate toward the melanoma stage correlated with the serum level of ANGPT2. TIE-2 M-MDSC from melanoma patients overexpressed immune suppressive molecules such as PD-L1, CD73, TGF-β, and IL-10, suggesting a highly immunosuppressive phenotype. The exposition of these cells to ANGPT2 increased the expression of most of these molecules, mainly Arginase 1. Hence, we observed a profound impairment of melanoma-specific T-cell responses in patients harboring high levels of TIE-2 M-MDSC along with ANGPT2. This was confirmed by experiments indicating that the addition of ANGPT2 increased the ability of TIE-2 M-MDSC to suppress antitumor T-cell function. Furthermore, by using TIE-2 kinase-specific inhibitors such as regorafenib or rebastinib, we demonstrated that an active TIE-2 signaling was required for optimal suppressive activity of these cells after ANGPT2 exposition. Collectively, these results support that TIE-2 M-MDSC/ANGPT2 axis represents a potential immune escape mechanism in melanoma.
Mots clés
ANGPT2, M-MDSCs, melanoma, tie-2, tumor antigen
Référence
Front Immunol. 2022 07 22;13:932298