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<p>Chimeric antigen receptor (CAR) T cell therapy demonstrates suboptimal efficacy in T-cell acute lymphoblastic leukemia (T-ALL), largely due to target-mediated fratricide from shared antigen expression and effector T cell exhaustion. The Mucin1-Thomsen-nouvelle (MUC1-Tn) antigen is overexpressed in various malignancies, including T-ALL. In this study, we confirmed MUC1-Tn protein expression in T-ALL cell lines and primary patient-derived bone marrow cells and subsequently developed MUC1-Tn-targeted CAR T cells. These CAR T cells effectively lysed T-ALL cells in both in vitro cytotoxicity assays and xenograft models. Given the critical role of the PI3Kδ signaling pathway in modulating T-cell function and tumor immunosuppression, we combined MUC1-Tn CAR T cells with the PI3Kδ inhibitor linperlisib. Linperlisib enhanced the anti-leukemic efficacy and persistence of MUC1-Tn CAR T cells. This was associated with reduced T cell exhaustion marker expression, decreased proportions of terminally differentiated cells, and sustained tumor control upon rechallenge. Furthermore, linperlisib induced mitochondrial fusion and enhanced respiratory capacity in CAR T cells. Mechanistically, this enhanced persistence was attributed to linperlisib-mediated suppression of Dual Specificity Phosphatase 2 (DUSP2) and its upstream transcription factor Early Growth Response 1 (EGR1).</p><p></p>

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Linperlisib enhances MUC1-Tn CAR T cell efficacy by inhibiting EGR1/DUSP2 axis to prevent CAR T cell exhaustion

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月3日

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  • Jia-Yue Wei,
  • Zi-Wei Liu,
  • Qi-Si Lu,
  • Yin-Jie Qin,
  • Ying-Zhi He,
  • Ye-Qin Zheng,
  • Yu-Chang Lin,
  • Dong-Hua Yang,
  • Yu-Hua Li,
  • Yu-Xian Huang

摘要

Chimeric antigen receptor (CAR) T cell therapy demonstrates suboptimal efficacy in T-cell acute lymphoblastic leukemia (T-ALL), largely due to target-mediated fratricide from shared antigen expression and effector T cell exhaustion. The Mucin1-Thomsen-nouvelle (MUC1-Tn) antigen is overexpressed in various malignancies, including T-ALL. In this study, we confirmed MUC1-Tn protein expression in T-ALL cell lines and primary patient-derived bone marrow cells and subsequently developed MUC1-Tn-targeted CAR T cells. These CAR T cells effectively lysed T-ALL cells in both in vitro cytotoxicity assays and xenograft models. Given the critical role of the PI3Kδ signaling pathway in modulating T-cell function and tumor immunosuppression, we combined MUC1-Tn CAR T cells with the PI3Kδ inhibitor linperlisib. Linperlisib enhanced the anti-leukemic efficacy and persistence of MUC1-Tn CAR T cells. This was associated with reduced T cell exhaustion marker expression, decreased proportions of terminally differentiated cells, and sustained tumor control upon rechallenge. Furthermore, linperlisib induced mitochondrial fusion and enhanced respiratory capacity in CAR T cells. Mechanistically, this enhanced persistence was attributed to linperlisib-mediated suppression of Dual Specificity Phosphatase 2 (DUSP2) and its upstream transcription factor Early Growth Response 1 (EGR1).