Single-cell ATAC-seq maps the comprehensive and dynamic chromatin accessibility landscape of CAR-T cell dysfunction

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 therap...

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Bibliographic Details
Published in:Leukemia 2022-11, Vol.36 (11), p.2656-2668
Main Authors: Jiang, Penglei, Zhang, Zhaoru, Hu, Yongxian, Liang, Zuyu, Han, Yingli, Li, Xia, Zeng, Xin, Zhang, Hao, Zhu, Meng, Dong, Jian, Huang, He, Qian, Pengxu
Format: Article
Language:English
Subjects:
Accessibility
Antigens
Cell culture
Cell differentiation
Chimeric antigen receptors
Chromatin
Chromatin - genetics
Chromatin - metabolism
Chromatin Immunoprecipitation Sequencing
Epigenetics
Humans
Immunotherapy, Adoptive
In vivo methods and tests
Interferon regulatory factor 4
Lymphocytes
Lymphocytes T
Neoplasm Recurrence, Local - metabolism
Receptors, Chimeric Antigen - genetics
Receptors, Chimeric Antigen - metabolism
Regulatory mechanisms (biology)
T-Lymphocytes
Tumor cells
Tumors
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Summary: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.
ISSN:0887-6924
1476-5551
DOI:10.1038/s41375-022-01676-0