Loss of RBMS1 promotes anti-tumor immunity through enabling PD-L1 checkpoint blockade in triple-negative breast cancer

Zhang, Jinrui1,2; Zhang, Ge3; Zhang, Wenjing1,2; Bai, Lu1,2; Wang, Luning1,2; Li, Tiantian1,2; Yan, Li3,4; Xu, Yang4; Chen, Dan5; Gao, Wenting6; Gao, Chuanzhou1,2; Chen, Chaoqun1,2; Ren, Menglin1,2; Jiao, Yuexia1,2; Qin, Hongqiang7; Sun, Yu1,2; Zhi, Lili1,2; Qi, Yangfan1,2; Zhao, Jinyao1,2; Liu, Quentin1,2; Liu, Han1,2; Wang, Yang1,2

2022-05-01

10.1038/s41418-022-01012-0

CELL DEATH AND DIFFERENTIATION   影响因子和分区

1350-9047

1476-5403

Immunotherapy has been widely utilized in multiple tumors, however, its efficacy in the treatment of triple-negative breast cancers (TNBC) is still being challenged. Meanwhile, functions and mechanisms of RNA binding proteins in regulating immunotherapy for TNBC remain largely elusive. Here we reported that the RNA binding protein RBMS1 is prevalent among immune-cold TNBC. Through a systematic shRNA-mediated screen, we found depletion of RBMS1 significantly reduced the level of programmed death ligand 1 (PD-L1) in TNBC. Clinically, RBMS1 was increased in breast cancer and its level was positively correlated to that of PD-L1. RBMS1 ablation stimulated cytotoxic T cell mediated anti-tumor immunity. Mechanistically, RBMS1 regulated the mRNA stability of B4GALT1, a newly identified glycosyltransferase of PD-L1. Depletion of RBMS1 destabilized the mRNA of B4GALT1, inhibited the glycosylation of PD-L1 and promoted the ubiquitination and subsequent degradation of PD-L1. Importantly, combination of RBMS1 depletion with CTLA4 immune checkpoint blockade or CAR-T treatment enhanced anti-tumor T-cell immunity both in vitro and in vivo. Together, our findings provided a new immunotherapeutic strategy against TNBC by targeting the immunosuppressive RBMS1.

SCI

英语

其他

National Natural Science Foundation of China[81830088,81422038,91540110,31471235,81872247,31400726,81402549] ; Liaoning Revitalization Talents Program[XLYC1802067] ; Department of Education of Liaoning Province[LZ2020050] ; Department of Science and Technology of Liaoning Province[2021JH6/10500160] ; Natural Science Foundation of Liaoning[2021-BS-213] ; Dalian High Level Talents Renovation Supporting Program[2019RQ097] ; Youth Innovation Promotion Association of CAS[2018212]

Biochemistry & Molecular Biology ; Cell Biology

Biochemistry & Molecular Biology ; Cell Biology

WOS:000792986600001

SPRINGERNATURE

MOLECULAR BIOLOGY & GENETICS

Web of Science

1.Dalian Med Univ, Inst Canc Stem Cells, Dalian 116044, Peoples R China
2.Dalian Med Univ, Affiliated Hosp 2, Dalian 116044, Peoples R China
3.Dalian Med Univ, Coll Basic Med Sci, Dept Immunol, Dalian 116044, Peoples R China
4.Southern Univ Sci & Technol, Sch Med, Shenzhen 518035, Peoples R China
5.Dalian Med Univ, Affiliated Hosp 1, Dept Pathol, Dalian 116044, Peoples R China
6.Dalian Med Univ, Inst Genome Engn Anim Models Human Dis, Dalian 116044, Peoples R China
7.Chinese Acad Sci, Dalian Inst Chem Phys, CAS Key Lab Separat Sci Analyt Chem, Dalian 116023, Peoples R China

Zhang, Jinrui,Zhang, Ge,Zhang, Wenjing,et al. Loss of RBMS1 promotes anti-tumor immunity through enabling PD-L1 checkpoint blockade in triple-negative breast cancer[J]. CELL DEATH AND DIFFERENTIATION,2022.

Zhang, Jinrui.,Zhang, Ge.,Zhang, Wenjing.,Bai, Lu.,Wang, Luning.,...&Wang, Yang.(2022).Loss of RBMS1 promotes anti-tumor immunity through enabling PD-L1 checkpoint blockade in triple-negative breast cancer.CELL DEATH AND DIFFERENTIATION.

Zhang, Jinrui,et al."Loss of RBMS1 promotes anti-tumor immunity through enabling PD-L1 checkpoint blockade in triple-negative breast cancer".CELL DEATH AND DIFFERENTIATION (2022).