Journal
ONCOIMMUNOLOGY
Volume 10, Issue 1, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2020.1866287
Keywords
T cell activation; chimeric antigen receptor; single-cell transcriptomics; CAR-T exhaustion
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Funding
- Cancer Research UK [C1163/A21762]
- Blood Cancer UK [12029]
- Wellcome Trust [Wellcome Senior Investigator Award] [206328/Z/17/Z]
- MRC [MR/M008975/1] Funding Source: UKRI
- Wellcome Trust [206328/Z/17/Z] Funding Source: Wellcome Trust
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This study used single-cell transcriptomic analysis to characterize the molecular features of CAR T cell activation, revealing several subpopulations of cells in CAR products with reproducible cellular composition across donors. Targeted data interrogation also showed that a small proportion of antigen-responding CAR-expressing cells exhibited exhaustion signatures with known markers and previously unassociated genes.
Chimeric antigen receptor (CAR) T-cell adoptive therapy is set to transform the treatment of a rapidly expanding range of malignancies. Although the activation process of normal T cells is well characterized, comparatively little is known about the activation of cells via the CAR. Here we have used flow cytometry together with single-cell transcriptome profiling to characterize the starting material (peripheral blood mononuclear cells) and CAR therapeutic products of 3 healthy donors in the presence and absence of antigen-specific stimulation. Analysis of 53,191 single-cell transcriptomes showed APRIL-based CAR products to contain several subpopulations of cells, with cellular composition reproducible from donor to donor, and all major cellular subsets compatible with CAR expression. Only 50% of CAR-expressing cells displayed transcriptional changes upon CAR-specific antigen exposure. The resulting molecular signature for CAR T-cell activation provides a rich resource for future dissection of underlying mechanisms. Targeted data interrogation also revealed that a small proportion of antigen-responding CAR-expressing cells displayed an exhaustion signature, with both known markers and genes not previously associated with T-cell exhaustion. Comprehensive single-cell transcriptomic analysis thus represents a powerful way to guide the assessment and optimization of clinical-grade CAR-T-cells, and inform future research into the underlying molecular processes.
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