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| Status |
Public on Apr 05, 2024 |
| Title |
B cell directed CAR-T cell therapy results in activation of CD8+ cytotoxic CAR-negative bystander T cells in both non-human primates and patients |
| Organism |
Macaca mulatta |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
There is growing appreciation for the emergence of CARneg bystander T cells after CAR-T cell infusion. However, their phenotypic and transcriptomic hallmarks and mechanisms of activation remain uncertain. We performed single-cell RNA-Seq (scRNA-Seq) on non-human primate (NHP) and patient-derived T cells to interrogate CARneg T cells following B cell targeted CAR-T cell therapy. In a NHP model, we observed a distinct population of activated CD8+ CARneg T cells emerging during CAR-T cell expansion. These bystander CD8+ CARneg T cells exhibited a unique transcriptional signature with upregulation of NK-cell markers (KIR3DL2, CD160, KLRD1), chemokines and chemokine receptors (CCL5, XCL1, CCR9), and downregulation of naive T cell-associated genes (SELL, CD28). A transcriptionally similar population was identified in patients following Tisangelecleucel infusion. Mechanistic studies revealed that IL-2 and IL-15 exposure induced bystander-like CD8+ T cells. These T cells efficiently killed leukemic cells through a TCR-independent mechanism. Together, these data identify bystander CD8+ T cells as a novel mechanism by which CAR-T cell infusion can induce further anti-leukemic activity, measurable in both NHP and in patients.
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| |
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| Overall design |
scRNA-Seq of peripheral blood T cells obtained from NHPs undergoing CAR-T treatment
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| Contributor(s) |
Kaminski J, Fleming R, Gerdemann U |
| Citation missing |
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| |
| Submission date |
Oct 15, 2023 |
| Last update date |
Apr 05, 2024 |
| Contact name |
Jim Kaminski |
| E-mail(s) |
James.Kaminski@childrens.harvard.edu
|
| Organization name |
Boston Children's Hospital
|
| Street address |
1 Blackfan Circle
|
| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02115 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL27943 |
Illumina NovaSeq 6000 (Macaca mulatta) |
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| Samples (35)
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| Relations |
| BioProject |
PRJNA1028316 |
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