期刊
LEUKEMIA
卷 36, 期 11, 页码 2656-2668出版社
SPRINGERNATURE
DOI: 10.1038/s41375-022-01676-0
关键词
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资金
- National Key R&D Program of China, Stem Cell and Translation Research [2018YFA0109300]
- Zhejiang Province Science Foundation for Distinguished Young Scholars [LR19H080001]
- Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang [2020R01006]
- National Natural Science Foundation of China [81870080, 91949115, 82000187, 81900176]
CAR-T cell therapy has achieved remarkable success in treating hematopoietic malignancies. However, CAR-T cell exhaustion leading to high relapse rate and poor persistence remains a major barrier. This study investigated the mechanisms of CAR-T exhaustion through single-cell ATAC-seq and identified BATF and IRF4 as pivotal regulators. Knockdown of BATF or IRF4 improved killing ability, inhibited exhaustion, and prolonged CAR-T cell persistence in vivo.
Chimeric antigen receptor T cells (CAR-T) therapy has achieved remarkable therapeutic success in treating a variety of hematopoietic malignancies. However, the high relapse rate and poor in vivo persistence, partially caused by CAR-T cell exhaustion, are still important barriers against CAR-T therapy. It remains largely elusive on the mechanisms of CAR-T exhaustion and how to attenuate exhaustion to achieve better therapeutic efficacy. In this study, we initially observed that CAR-T cells showed rapid differentiation and increased exhaustion after co-culture with tumor cells in vitro, and then performed single-cell ATAC-seq to depict the comprehensive and dynamic landscape of chromatin accessibility of CAR-T cells during tumor cell stimulation. Analyses of differential chromatin accessible regions and motif accessibility revealed that TFs were distinct in each cell type and reconstituted a coordinated regulatory network to drive CAR-T exhaustion. Furthermore, we performed scATAC-seq in patient-derived CAR-T cells and identified BATF and IRF4 as pivotal regulators in CAR-T cell exhaustion. Finally, knockdown of BATF or IRF4 enhanced the killing ability, inhibited exhaustion, and prolonged the persistence of CAR-T cells in vivo. Together, our study unraveled the epigenetic regulatory mechanisms of CAR-T exhaustion and provided new insights into CAR-T engineering to achieve better clinical treatment benefits.
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