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| Status |
Public on Sep 06, 2023 |
| Title |
Ibrutinib effects on in vitro exhausted CTL |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
CTL exhaustion is driven by chronic antigen stimulation and is characterized by specific molecular, phenotypic and functional changes. Reversing CTLs exhaustion with immune checkpoint blockade (ICB) has provided clinical benefits in different types of cancer. However, the therapeutic effects of ICB varies among patients and cancer types. Ibrutinib, a potent BTK inhibitor, is reported that it improved T cell function in ibrutinib long-term treated chronic lymphocytic leukemia patients. However, the mechanism remains unclear. We hypothesized ibrutinib can directly act on CD8+ T cells and reinvigorates exhausted CTLs. To test this, we generated in vitro exhausted OT-I cells as previously described (Zhao M et al PLoS Pathog. 16(6): e1008555) by repeatedly stimulating cells with SIINFEKL peptide. We tested the effect of ibrutinib on inhibitory receptor, exhaustion-related transcription factor expression and cytokine (IFNγ, TNFα and IL-2) production. We found that ibrutinib decreased the expression of multiple inhibitory receptors on in vitro exhausted CTL while the critical transcription factor, Tox was downregulated. The cytokine production of exhausted cells was partially improved after ibrutinib treatment. Importantly, using btk deficient mice we found the effect of ibrutinib was independent of BTK expression. To conclude, these findings suggest that ibrutinib reduces CTL exhaustion. Our study provides evidence for ibrutinib’s synergistic use with cancer immunotherapy.
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| Overall design |
CD8+ T cells are first exhausted in vitro for 5 days, then treated with either DMSO or Ibrutinib for 3 days before RNA isolation and sequencing.
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| Contributor(s) |
Li L, Zhao M, Grashof D, van de Werken H, Katsikis P |
| Citation(s) |
37771591 |
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| Submission date |
Dec 07, 2022 |
| Last update date |
Dec 07, 2023 |
| Contact name |
Peter D. Katsikis |
| E-mail(s) |
p.katsikis@erasmusmc.nl
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| Organization name |
Erasmus University Medical Center
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| Department |
Department of Immunology
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| Street address |
Dr. Molewaterplein 40
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| City |
Rotterdam |
| State/province |
Zuid-Holland |
| ZIP/Postal code |
3015 GD |
| Country |
Netherlands |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (20)
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| Relations |
| BioProject |
PRJNA909657 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE220433_AllGenes_r_BTK_vs_r_DMSO.xlsx |
4.9 Mb |
(ftp)(http) |
XLSX |
| GSE220433_Annotated_DEgenes_r_BTK_vs_r_DMSO.xlsx |
477.0 Kb |
(ftp)(http) |
XLSX |
| GSE220433_RAW.tar |
18.0 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
| Processed data are available on Series record |
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