CAR-engineered lymphocyte persistence is governed by a FAS ligand–FAS autoregulatory circuit Journal Article
| Authors: | Yi, F.; Cohen, T.; Zimmerman, N.; Dündar, F.; Zumbo, P.; Eltilib, R.; Brophy, E. J.; Arkin, H.; Feucht, J.; Gormally, M. V.; Hackett, C. S.; Kropp, K. N.; Etxeberria, I.; Chandran, S. S.; Zhao, Z.; Cai, W.; Daniyan, A. F.; Park, J. H.; Lareau, C. A.; Hsu, K. C.; Sadelain, M.; Betel, D.; Klebanoff, C. A. |
| Article Title: | CAR-engineered lymphocyte persistence is governed by a FAS ligand–FAS autoregulatory circuit |
| Abstract: | Chimeric antigen receptor (CAR)-engineered lymphocytes treat B cell malignancies; however, limited persistence can restrain the full therapeutic potential of this approach. FAS ligand (FAS-L)/FAS interactions govern lymphocyte homeostasis. Knowledge of which cells express FAS-L in patients with cancer and whether these sources compromise CAR persistence remains incomplete. Here, we constructed a single-cell atlas of diverse cancers to identify cellular subsets expressing FASLG, the gene encoding FAS-L. We discovered that FASLG expression is limited primarily to endogenous T cells, natural killer (NK) cells and CAR-T cells, while tumor and stromal cell expression is minimal. To establish whether CAR-T and CAR-NK cell survival is FAS-L regulated, we performed competitive fitness assays using FAS-dominant negative receptor (ΔFAS)-modified lymphocytes. Following transfer, ΔFAS-expressing CAR-T/CAR-NK cells became enriched, a phenomenon that mechanistically was reverted through FASLG knockout. By contrast, FASLG was dispensable for CAR-mediated tumor killing. In multiple models in female mice, ΔFAS coexpression enhanced antitumor efficacy. Together, these findings reveal that CAR-engineered lymphocyte persistence is governed by a FAS-L/FAS autoregulatory circuit. © The Author(s) 2025. |
| Journal Title: | Nature Cancer |
| ISSN: | 2662-1347 |
| Publisher: | Nature Research |
| Publication status: | Online ahead of print |
| Date Published: | 2025-07-22 |
| Online Publication Date: | 2025-07-22 |
| Language: | English |
| DOI: | 10.1038/s43018-025-01009-x |
| PROVIDER: | scopus |
| PUBMED: | 40696154 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Christopher A. Klebanoff -- Source: Scopus |
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