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| Status |
Public on Apr 12, 2022 |
| Title |
Orthogonal Gene Engineering Enables Novel Synthetic States of Powerful Tumor-rejecting CD8+ T Cells Escaping Canonical Exhaustion |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
To date, no immunotherapy approaches have managed to fully overcome T-cell exhaustion, which remains a mandatory fate for chronically activated effector cells and a major therapeutic challenge. Understanding how to reprogram CD8+ TILs away from exhausted effector states remains an elusive goal. Our work provides for the first-time evidence that orthogonal gene-engineering of T cells to secrete an IL-2-variant binding the IL-2R and the alarmin IL-33 reprogrammed adoptively transferred T cells to acquire a novel, synthetic state, which deviated from canonical exhaustion and displayed superior effector functions. These cells successfully overcame homeostatic barriers in the host, and led – in the absence of lymphodepletion or exogenous cytokine support – to high levels of engraftment and tumor regression. Our work unlocks the novel opportunity of rationally engineering synthetic CD8+ T-cell states endowed with the ability to avoid exhaustion and control advanced solid tumors.
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| Overall design |
CD45+ bulk TILs were independently sorted at at days 5 (T1), 12 (T2) and 26 (T3) post cell transfer
Groups: Non-Treated tumor-bearing mice (G5); Mice received ACT using Untransduced OT1 T cells (G1);Mice received ACT using PD1d/IL2V-secreting OT1 (G2); Mice received ACT using PD1d/33-secreting OT1 (G3); Mice received ACT using PD1d/2V/33-secreting OT1 (G4)
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| Contributor(s) |
Corria-Osorio J, Carmona SJ, Andreatta M, Coukos G |
| Citation(s) |
37081150 |
| |
| Submission date |
Apr 09, 2022 |
| Last update date |
Apr 25, 2023 |
| Contact name |
Jesus Corria-Osorio |
| E-mail(s) |
angeldejesus.corriaosorio@unil.ch
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| Phone |
0216925964
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| Organization name |
Ludwig Institute for Cancer Research. Lausanne Branch. UNIL
|
| Department |
Department of Fundamental Oncology
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| Lab |
System T cells (George Coukos' Lab)
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| Street address |
Chemin des Boveresses 155
|
| City |
Lausanne |
| State/province |
Vaud |
| ZIP/Postal code |
1066 |
| Country |
Switzerland |
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| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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| Samples (8)
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| Relations |
| BioProject |
PRJNA825099 |
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