LILRB2 通过增强 HLA-A 降解促进乳腺癌细胞的免疫逃逸。

LILRB2 promotes immune escape in breast cancer cells via enhanced HLA-A degradation.

机构信息

Department of Internal Oncology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, China.

Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Huangpu District, 200025, Shanghai, China.

出版信息

Cell Oncol (Dordr). 2024 Oct;47(5):1679-1696. doi: 10.1007/s13402-024-00947-5. Epub 2024 Apr 24.

DOI:10.1007/s13402-024-00947-5

PMID:38656573

Abstract

PURPOSE

Increased expression of leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) is associated with immune evasion in breast cancer (BC). The aim of this study to elucidate the role of LILRB2 in BC progression.

METHODS

LILRB2 expression in tumor tissues was detected by immunohistochemical staining. Human leukocyte antigen A (HLA-A) expression in BC cells was detected by Western blotting, and HLA-A ubiquitination was detected by immunoprecipitation and histidine pulldown assay. An in-situ tumor model was established in nude BALB/c mice to verify the role of LILRB2 in immune escape. Finally, the functions and potential mechanisms of LILRB2 in BC progression were explored using in silico data.

RESULTS

LILRB2 was upregulated in BC tissues and cells, and correlated positively with poor prognosis. LILRB2 promoted BC progression by downregulating HLA-A expression. Mechanistically, LILRB2 facilitates the ubiquitination and subsequent degradation of HLA-A by promoting the interaction between the ubiquitin ligase membrane-associated ring finger protein 9 (MARCH9) and HLA-A. In syngeneic graft mouse models, LILRB2-expressing BC cells evaded CD8 + T cells and inhibited the secretion of cytokines by the cytotoxic CD8 + T cells.

CONCLUSION

LILRB2 downregulates HLA-A to promote immune evasion in BC cells and is a promising new target for BC treatment.

摘要

目的

白细胞免疫球蛋白样受体亚家族 B 成员 2（LILRB2）的表达增加与乳腺癌（BC）中的免疫逃逸有关。本研究旨在阐明 LILRB2 在 BC 进展中的作用。

方法

通过免疫组织化学染色检测肿瘤组织中的 LILRB2 表达。通过 Western blot 检测 BC 细胞中的人类白细胞抗原 A（HLA-A）表达，通过免疫沉淀和组氨酸下拉实验检测 HLA-A 泛素化。在裸鼠 BALB/c 中建立原位肿瘤模型，以验证 LILRB2 在免疫逃逸中的作用。最后，使用计算机数据探讨了 LILRB2 在 BC 进展中的功能和潜在机制。

结果

LILRB2 在 BC 组织和细胞中上调，与预后不良呈正相关。LILRB2 通过下调 HLA-A 表达促进 BC 进展。机制上，LILRB2 通过促进泛素连接酶膜相关环指蛋白 9（MARCH9）和 HLA-A 之间的相互作用，促进 HLA-A 的泛素化和随后降解，从而促进 BC 的进展。在同基因移植小鼠模型中，表达 LILRB2 的 BC 细胞逃避 CD8+T 细胞，并抑制细胞毒性 CD8+T 细胞分泌细胞因子。