LILRB4 represents a promising target for immunotherapy by dual targeting tumor cells and myeloid-derived suppressive cells in multiple myeloma

被引:2
作者
Gong, Lixin [1 ,2 ]
Sun, Hao [1 ,2 ]
Liu, Lanting [1 ,2 ]
Sun, Xiyue [1 ,2 ]
Fang, Teng [1 ,2 ]
Yu, Zhen [1 ,2 ]
Sui, Weiwei [1 ,2 ]
Xu, Jingyu [1 ,2 ]
Wang, Tingyu [1 ,2 ]
Feng, Fangshuo [1 ,2 ]
Lei, Lei [3 ]
Rui, Wei [3 ]
Liu, Yuxuan [1 ,2 ]
Zhao, Xueqiang [4 ]
An, Gang [1 ,2 ]
Lin, Xin [3 ]
Qiu, Lugui [1 ,2 ]
Hao, Mu [1 ,2 ]
机构
[1] Chinese Acad Med Sci & Peking Union Med Coll, Inst Hematol & Blood Dis Hosp, Haihe Lab Cell Ecosyst, State Key Lab Expt Hematol,Natl Clin Res Ctr Blood, Tianjin, Peoples R China
[2] Tianjin Inst Hlth Sci, Tianjin, Peoples R China
[3] BriSTAR Immunotech Biotechnol Co Ltd, Beijing, Peoples R China
[4] Tsinghua Univ, Sch Med, Dept Basic Med Sci, Beijing, Peoples R China
基金
中国国家自然科学基金;
关键词
DRUG-RESISTANCE; ACTIVATION; EXPRESSION; BORTEZOMIB; THERAPY;
D O I
10.3324/haematol.2024.285099
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Multiple myeloma (MM) remains an incurable hematologic malignancy. Despite tremendous advances in the treatment of this disease, about 10% of patients still have very poor outcomes with a median overall survival of less than 24 months. Our study aimed to underscore the critical mechanisms pertaining to rapid disease progression and provide novel therapeutic choices for these ultrahigh-risk patients. We utilized single-cell transcriptomic sequencing to dissect the characteristic bone marrow niche of patients who survived less than 2 years (EM24). Notably, enrichment of a LILRB4high pre-mature plasma-cell cluster was observed in EM24 patients compared to patients with durable remission. This cluster exhibited aggressive proliferation and a drug-resistance phenotype. High levels of LILRB4 promoted MM clonogenicity and progression. Clinically, high expression of LILRB4 was correlated with poor prognosis in both newly diagnosed MM patients and relapsed/ refractory MM patients. ATAC-sequencing analysis identified that pronounced chromosomal accessibility caused the elevation of LILRB4 on MM cells. CRISPR-Cas9 deletion of LILRB4 alleviated the growth of MM cells, inhibited the immunosuppressive function of myeloid-derived suppressive cells (MDSC), and further rescued T-cell dysfunction in the MM microenvironment. Greater infiltration of MDSC was observed in EM24 patients. We therefore generated an innovative T-cell receptor-based chimeric antigen receptor T cell, LILRB4-STAR-T. Cytotoxicity experiments demonstrated that LILRB4-STAR-T cells efficaciously eliminated tumor cells and impeded MDSC function. In conclusion, our study elucidates that LILRB4 is an ideal biomarker and promising immunotherapy target for high-risk MM. LILRB4-STAR-T-cell immunotherapy is promising against both tumor cells and the immunosuppressive tumor microenvironment in MM.
引用
收藏
页码:3650 / 3669
页数:20
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