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<p>Nature killer (NK) cell plays a critical role in cancer immunosurveillance and is considered a potent immunotherapeutic tool for many cancers, including pancreatic ductal adenocarcinomas (PDACs). Increasing evidence suggests that cancer occurs with systemic immune perturbations. However, the effects of PDAC tumor burden on systemic NK cells remain poorly understood. PDAC tumor-bearing mice display decreased frequency and dysfunction of NKs the spleens. We identified an increase in Gr-1+ myeloid cells within the spleens, which negatively impacts both endogenous and adoptively transferred NK cell frequency and function. Apolipoprotein E (ApoE), a lipid metabolism regulator, is upregulated in Gr-1+ myeloid cells of tumor-bearing mice, promoting lipid oxidation and reactive oxygen species (ROS) generation. Genetic knockout of Apoe in Gr-1+ myeloid cells abrogate their suppressive effects on NK cell function. Furthermore, treatment with lipid metabolism inhibitors restores endogenous and adoptively transferred NKs’ effector function in the spleens and tumor microenvironment. These studies underscore the importance of understanding preexisting systemic alterations in PDAC patients before applying NK cell-based immunotherapies.</p>

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Systemic immunosuppression limits NK cell therapy efficacy in pancreatic cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月8日

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  • Chunbo He,
  • Dezhen Wang,
  • Tuo Hu,
  • Daisy Gonzalez,
  • Ravi Thakur,
  • Damian P. Matysniak,
  • Ryan J. King,
  • Sai Sundeep Kollala,
  • Spas Dimitrov Markov,
  • Yuki Fujii,
  • Gullanki Naga Venkata Charan Tej,
  • Junzhang Zhao,
  • Longyang Jin,
  • Rebecca Oberley-Deegan,
  • Surendra K. Shukla,
  • Xin A. Zhang,
  • Jacob E. Friedman,
  • Pankaj K. Singh,
  • Michael A. Hollingsworth,
  • Marina Pasca di Magliano,
  • Howard C. Crawford,
  • Kamiya Mehla

摘要

Nature killer (NK) cell plays a critical role in cancer immunosurveillance and is considered a potent immunotherapeutic tool for many cancers, including pancreatic ductal adenocarcinomas (PDACs). Increasing evidence suggests that cancer occurs with systemic immune perturbations. However, the effects of PDAC tumor burden on systemic NK cells remain poorly understood. PDAC tumor-bearing mice display decreased frequency and dysfunction of NKs the spleens. We identified an increase in Gr-1+ myeloid cells within the spleens, which negatively impacts both endogenous and adoptively transferred NK cell frequency and function. Apolipoprotein E (ApoE), a lipid metabolism regulator, is upregulated in Gr-1+ myeloid cells of tumor-bearing mice, promoting lipid oxidation and reactive oxygen species (ROS) generation. Genetic knockout of Apoe in Gr-1+ myeloid cells abrogate their suppressive effects on NK cell function. Furthermore, treatment with lipid metabolism inhibitors restores endogenous and adoptively transferred NKs’ effector function in the spleens and tumor microenvironment. These studies underscore the importance of understanding preexisting systemic alterations in PDAC patients before applying NK cell-based immunotherapies.