FOXP4-AS1 promotes CD8+ T cell exhaustion and esophageal cancer immune escape through USP10-stabilized PD-L1

被引:0
作者
Shen, Guo-yi [1 ]
Zhang, Yi [1 ]
Huang, Rong-zhi [1 ]
Huang, Zhi-yong [1 ]
Yang, Le-yi [1 ]
Chen, Ding-zhu [1 ]
Yang, Shao-bin [1 ]
机构
[1] Fujian Med Univ, Dept Cardiothorac Surg, Zhangzhou Affiliated Hosp, 59 Shengli West Rd, Zhangzhou 363000, Fujian, Peoples R China
关键词
FOXP4-AS1; PD-L1; USP10; Immune escape; Esophageal cancer;
D O I
10.1007/s12026-024-09482-9
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Esophageal cancer (EC) is the 9th most frequently diagnosed malignancy globally with unfavorable prognosis. Immune escape is one of the principal factors leading to poor survival, however, the mechanism underlying immune escape remains largely uninvestigated. The xenograft mouse model and EC cell-CD8(+) cytotoxic T lymphocytes (CTLs) co-culture system were established. Immunohistochemistry, qRT-PCR or western blot were employed to detect the levels of long non-coding RNA (lncRNA) FOXP4-AS1, PD-L1, USP10 and other molecules. The abundance of T cells, cytokine production and cell apoptosis were monitored by flow cytometry. The viability of CTLs was assessed by Trypan blue staining. The binding between FOXP4-AS1 and USP10 was validated by RNA pull-down assay, and the interaction between USP10 and PD-L1, as well as the ubiquitination of PD-L1, were detected by co-immunoprecipitation. The elevation of FOXP4-AS1 in EC was associated with decreased CTL abundance, and upregulated PD-L1 facilitated CTL apoptosis in EC. FOXP4-AS1 accelerated EC tumor growth by decreasing the abundance of tumor infiltrating CTLs in vivo. FOXP4-AS1 inhibited the viability of CTLs and facilitated the cytotoxicity and exhaustion of CTLs. In Kyse 450 cell-CTL co-culture system, FOXP4-AS1 suppressed the viability and abundance of CTLs, and inhibited EC cell apoptosis via PD-L1. Mechanistically, FOXP4-AS1 regulated the ubiquitination of PD-L1 through deubiquitinating enzyme USP10. FOXP4-AS1 promoted CTL exhaustion and EC immune escape through USP10-stabilized PD-L1.
引用
收藏
页码:766 / 775
页数:10
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