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<p>Allogeneic cellular immunotherapy exhibits promising efficacy for cancer treatment, but donor cell rejection remains a major barrier. Here, we systematically evaluate human leukocyte antigens (HLA) and immune checkpoints PD-L1, HLA-E, and CD47 in the rejection of allogeneic NK cells and identify CD8<sup>+</sup> T cells as the dominant cell type mediating allorejection. We demonstrate that a single gene construct that combines an shRNA that selectively interferes with HLA class I but not HLA-E expression, a chimeric antigen receptor (CAR), and PD-L1 or single-chain HLA-E (SCE) enables the one-step construction of allogeneic CAR-NK cells that evade host-mediated rejection both in vitro and in a xenograft mouse model. Furthermore, CAR-NK cells overexpressing PD-L1 or SCE effectively kill tumor cells through the upregulation of cytotoxic genes and reduced exhaustion and exhibit a favorable safety profile due to the decreased production of inflammatory cytokines involved in cytokine release syndrome. Thus, our approach represents a promising strategy in enabling “off-the-shelf” allogeneic cellular immunotherapies.</p>

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Selective HLA knockdown and PD-L1 expression prevent allogeneic CAR-NK cell rejection and enhance safety and anti-tumor responses in xenograft mice

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月8日

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  • Fuguo Liu,
  • Mubin Tarannum,
  • Yingjie Zhao,
  • Yiming J. Zhang,
  • James Dongjoo Ham,
  • Kewen Lei,
  • Yuhao Qiang,
  • Xingyu Deng,
  • Maily Nguyen,
  • Khanhlinh Dinh,
  • Shaobo Yang,
  • Alaa Kassim Ali,
  • Toni K. Choueiri,
  • Jerome Ritz,
  • Rizwan Romee,
  • Jianzhu Chen

摘要

Allogeneic cellular immunotherapy exhibits promising efficacy for cancer treatment, but donor cell rejection remains a major barrier. Here, we systematically evaluate human leukocyte antigens (HLA) and immune checkpoints PD-L1, HLA-E, and CD47 in the rejection of allogeneic NK cells and identify CD8+ T cells as the dominant cell type mediating allorejection. We demonstrate that a single gene construct that combines an shRNA that selectively interferes with HLA class I but not HLA-E expression, a chimeric antigen receptor (CAR), and PD-L1 or single-chain HLA-E (SCE) enables the one-step construction of allogeneic CAR-NK cells that evade host-mediated rejection both in vitro and in a xenograft mouse model. Furthermore, CAR-NK cells overexpressing PD-L1 or SCE effectively kill tumor cells through the upregulation of cytotoxic genes and reduced exhaustion and exhibit a favorable safety profile due to the decreased production of inflammatory cytokines involved in cytokine release syndrome. Thus, our approach represents a promising strategy in enabling “off-the-shelf” allogeneic cellular immunotherapies.