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<p>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 <i>FASLG</i>, the gene encoding FAS-L. We discovered that <i>FASLG</i> 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 <i>FASLG</i> knockout. By contrast, <i>FASLG</i> 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.</p>

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CAR-engineered lymphocyte persistence is governed by a FAS ligand–FAS autoregulatory circuit

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月22日

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  • Fei Yi,
  • Tal Cohen,
  • Natalie Zimmerman,
  • Friederike Dündar,
  • Paul Zumbo,
  • Razan Eltilib,
  • Erica J. Brophy,
  • Hannah Arkin,
  • Judith Feucht,
  • Michael V. Gormally,
  • Christopher S. Hackett,
  • Korbinian N. Kropp,
  • Inaki Etxeberria,
  • Smita S. Chandran,
  • Zeguo Zhao,
  • Winson Cai,
  • Anthony F. Daniyan,
  • Jae H. Park,
  • Caleb A. Lareau,
  • Katharine C. Hsu,
  • Michel Sadelain,
  • Doron Betel,
  • Christopher A. Klebanoff

摘要

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.