Helmholtz Gemeinschaft


Simultaneous genetic ablation of PD-1, LAG-3, and TIM-3 in CD8 T cells delays tumor growth and improves survival outcome

PDF (Original Article) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
[img] Other (Supporting Information)

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
Page Range:3207
Date:16 March 2022
Official Publication:https://doi.org/10.3390/ijms23063207
PubMed:View item in PubMed

Repository Staff Only: item control page


Downloads per month over past year

Open Access
MDC Library