Impaired death receptor signaling in leukemia causes antigen-independent resistance by inducing CAR T-cell dysfunction
- Title
- Impaired death receptor signaling in leukemia causes antigen-independent resistance by inducing CAR T-cell dysfunction
- Author
- 이용구
- Issue Date
- 2020-04
- Publisher
- American Association for Cancer Research Inc.
- Citation
- CANCER DISCOVERY, v. 10, no. 4, page. 552-567
- Abstract
- Primary resistance to CD19-directed chimeric antigen receptor T-cell therapy
(CART19) occurs in 10% to 20% of patients with acute lymphoblastic leukemia
(ALL); however, the mechanisms of this resistance remain elusive. Using a genome-wide loss-offunction screen, we identifi ed that impaired death receptor signaling in ALL led to rapidly progressive disease despite CART19 treatment. This was mediated by an inherent resistance to T-cell cytotoxicity that permitted antigen persistence and was subsequently magnifi ed by the induction of CAR T-cell functional impairment. These fi ndings were validated using samples from two CAR T-cell clinical trials in ALL, where we found that reduced expression of death receptor genes was associated with worse overall survival and reduced T-cell fi tness. Our fi ndings suggest that inherent dysregulation of death receptor signaling in ALL directly leads to CAR T-cell failure by impairing T-cell cytotoxicity and promoting progressive CAR T-cell dysfunction.
- URI
- https://cancerdiscovery.aacrjournals.org/content/10/4/552https://repository.hanyang.ac.kr/handle/20.500.11754/164556
- ISSN
- 2159-8290; 2159-8274
- DOI
- 10.1158/2159-8290.CD-19-0813
- Appears in Collections:
- COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
- Files in This Item:
There are no files associated with this item.
- Export
- RIS (EndNote)
- XLS (Excel)
- XML