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<p>Nearly all chimeric antigen receptors (CARs) signal in the absence of antigen, referred to as ‘tonic signaling’. Tonic signaling of CARs containing 41BB domains enhances T cell fitness and function, in contrast to the exhaustion driven by CD28-containing CARs. Here we show that 41BB induces BACH2, a transcriptional regulator that directs stem and memory programs. Overexpression of BACH2 successfully prevented exhaustion but locked CAR T cells in a quiescent state. We linked BACH2 to a degradation domain to tune BACH2, enabling us to prevent exhaustion while enabling potent effector function that broadly enhanced the long-term efficacy of CAR T cells targeting liquid and solid tumors. Through interrogation of clinical CAR products, we further found an association between BACH2 activity and clinical outcomes in patients with leukemia. These data identify a central function for BACH2 in regulating CAR T cell efficacy.</p>

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BACH2 regulates T cell lineage state to enhance CAR T cell function

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月16日

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  • Tien-Ching Chang,
  • Amanda Heard,
  • John Lattin,
  • John M. Warrington,
  • Amanda Barrett,
  • Jack H. Landmann,
  • Yangdon Tenzin,
  • Vishaal Ganesh,
  • Bryant Thompson,
  • Sadia Afrin,
  • Deepesh Kumar Gupta,
  • Ju-Fang Chang,
  • Julie Ritchey,
  • Mehmet Emrah Selli,
  • Yu-Sung Hsu,
  • Haorui Song,
  • A. J. Federico,
  • Avery Horn,
  • Michael P. Meers,
  • Evan W. Weber,
  • Thomas J. Wandless,
  • Jeremy Chase Crawford,
  • Paul G. Thomas,
  • John F. DiPersio,
  • Stephen Gottschalk,
  • Nathan Singh

摘要

Nearly all chimeric antigen receptors (CARs) signal in the absence of antigen, referred to as ‘tonic signaling’. Tonic signaling of CARs containing 41BB domains enhances T cell fitness and function, in contrast to the exhaustion driven by CD28-containing CARs. Here we show that 41BB induces BACH2, a transcriptional regulator that directs stem and memory programs. Overexpression of BACH2 successfully prevented exhaustion but locked CAR T cells in a quiescent state. We linked BACH2 to a degradation domain to tune BACH2, enabling us to prevent exhaustion while enabling potent effector function that broadly enhanced the long-term efficacy of CAR T cells targeting liquid and solid tumors. Through interrogation of clinical CAR products, we further found an association between BACH2 activity and clinical outcomes in patients with leukemia. These data identify a central function for BACH2 in regulating CAR T cell efficacy.