TIE-2 Signaling Activation by Angiopoietin 2 On Myeloid-Derived Suppressor Cells Promotes Melanoma-Specific T-cell Inhibition

被引:8
|
作者
Marguier, Amelie [1 ]
Laheurte, Caroline [1 ,2 ]
Lecoester, Benoit [1 ]
Malfroy, Marine [1 ]
Boullerot, Laura [1 ,2 ]
Renaudin, Adeline [2 ]
Seffar, Evan [1 ]
Kumar, Abhishek [1 ]
Nardin, Charlee [1 ,3 ]
Aubin, Francois [1 ,3 ]
Adotevi, Olivier [1 ,2 ,4 ]
机构
[1] Univ Bourgogne Franche Comte, INSERM, EFS BFC, UMR1098,RIGHT Interact Greffon Hote Tumeur Ingn Ce, Besancon, France
[2] INSERM C 1431, Clin Invest Ctr Biotherapy, Plateforme Biomonitoring, Besancon, France
[3] Univ Hosp Besancon, Dept Dermatol, Besancon, France
[4] CHU Besancon, Serv Oncol medicale, Besancon, France
来源
FRONTIERS IN IMMUNOLOGY | 2022年 / 13卷
关键词
ANGPT2; tumor antigen; melanoma; tie-2; M-MDSCs; TIE2-EXPRESSING MONOCYTES; TUMOR; EXPRESSION; IMMUNITY; CANCER; ANGIOGENESIS; MACROPHAGES; METASTASIS; HYPOXIA; BLOCKS;
D O I
10.3389/fimmu.2022.932298
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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-beta, 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 in vitro 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.
引用
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页数:10
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