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| Item Type: | Article |
|---|---|
| Title: | Simultaneous genetic ablation of PD-1, LAG-3, and TIM-3 in CD8 T cells delays tumor growth and improves survival outcome |
| Creators Name: | Ciraolo, E. and Althoff, S. and Ruß, J. and Rosnev, S. and Butze, M. and Pühl, M. and Frentsch, M. and Bullinger, L. and Na, I.K. |
| Abstract: | Immune checkpoint inhibitors (ICI) represented a step forward in improving the outcome of patients with various refractory solid tumors and several therapeutic regimens incorporating ICI have already been approved for a variety of tumor entities. However, besides remarkable long-term responses, checkpoint inhibition can trigger severe immune-related adverse events in some patients. In order to improve safety of ICI as well as T cell therapy, we tested the feasibility of combining T cell-based immunotherapy with genetic disruption of checkpoint molecule expression. Therefore, we generated H-Y and ovalbumin antigen-specific CD8(+) T cells with abolished PD-1, LAG-3, and TIM-3 expression through CRISPR/Cas9 technology. CD8(+) T cells, subjected to PD-1, LAG-3, and TIM-3 genetic editing, showed a strong reduction in immune checkpoint molecule expression after in vitro activation, while no relevant reduction in responsiveness to in vitro stimulation was observed. At the same time, in B16-OVA tumor model, transferred genetically edited OT-1 CD8(+) T cells promoted longer survival compared to control T cells and showed enhanced expansion without associated toxicity. Our study supports the notion that antigen-specific adoptive T cell therapy with concomitant genetic disruption of multiple checkpoint inhibitory receptors could represent an effective antitumor immunotherapy approach with improved tolerability profile. |
| Keywords: | Adoptive Immunotherapy, T Lymphocytes, CRISPR/Cas9, Checkpoint Inhibitory Molecule |
| Source: | International Journal of Molecular Sciences |
| ISSN: | 1422-0067 |
| Publisher: | MDPI |
| Volume: | 23 |
| Number: | 6 |
| Page Range: | 3207 |
| Date: | 16 March 2022 |
| Official Publication: | https://doi.org/10.3390/ijms23063207 |
| PubMed: | View item in PubMed |
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