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Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness
Chun-Pu Lin1, Pierre L Levy2, Astrid Alflen3
1Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
Abstract:
Genes limiting T cell antitumor activity may serve as therapeutic targets. It has not been systematically studied whether there are regulators that uniquely or broadly contribute to T cell fitness. We perform genome-scale CRISPR-Cas9 knockout screens in primary CD8 T cells to uncover genes negatively impacting fitness upon three modes of stimulation: (1) intense, triggering activation-induced cell death (AICD); (2) acute, triggering expansion; (3) chronic, causing dysfunction. Besides established regulators, we uncover genes controlling T cell fitness either specifically or commonly upon differential stimulation. Dap5 ablation, ranking highly in all three screens, increases translation while enhancing tumor killing. Loss of Icam1-mediated homotypic T cell clustering amplifies cell expansion and effector functions after both acute and intense stimulation. Lastly, Ctbp1 inactivation induces functional T cell persistence exclusively upon chronic stimulation. Our results functionally annotate fitness regulators based on their unique or shared contribution to traits limiting T cell antitumor activity.
Insights
Identifying genes that regulate T cell fitness is crucial for cancer immunotherapy. This study reveals novel regulators of T cell function under different stimulation conditions, offering new therapeutic targets to enhance anti-tumor activity.
Area of Science:
- Immunology
- Molecular Biology
- Cancer Research
Background:
- T cells are critical for anti-tumor immunity.
- Identifying regulators of T cell fitness is essential for developing effective cancer immunotherapies.
- Systematic studies on genes uniquely or broadly impacting T cell fitness are lacking.
Purpose of the Study:
- To uncover genes that regulate T cell fitness under various stimulation conditions.
- To identify novel therapeutic targets for enhancing T cell-mediated anti-tumor activity.
Main Methods:
- Genome-scale CRISPR-Cas9 knockout screens were performed on primary CD8 T cells.
- Cells were subjected to three distinct stimulation modes: intense (activation-induced cell death), acute (expansion), and chronic (dysfunction).
- Gene functions were analyzed based on their impact on T cell fitness across different stimulations.
Main Results:
- Several novel regulators of T cell fitness were identified, in addition to known ones.
- Dap5 ablation enhanced translation and tumor killing across all tested conditions.
- Loss of Icam1-mediated T cell clustering boosted expansion and effector functions.
- Ctbp1 inactivation promoted functional T cell persistence specifically under chronic stimulation.
Conclusions:
- This study functionally annotates regulators of T cell fitness based on their specific or shared contributions to anti-tumor activity.
- The identified genes, such as Dap5, Icam1, and Ctbp1, represent potential therapeutic targets for improving cancer immunotherapy.
- Understanding these regulators provides insights into T cell responses to different immune challenges.
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