| First Author | Lin CP | Year | 2024 |
| Journal | Cancer Cell | Volume | 42 |
| Issue | 4 | Pages | 623-645.e10 |
| PubMed ID | 38490212 | Mgi Jnum | J:391682 |
| Mgi Id | MGI:7615993 | Doi | 10.1016/j.ccell.2024.02.016 |
| Citation | Lin CP, et al. (2024) Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness. Cancer Cell |
| abstractText | 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. |
