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Updated: Jul 10, 2026
Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
Published on: January 17, 2025
Systemic immunosuppression limits NK cell therapy efficacy in pancreatic cancer
Chunbo He1, Dezhen Wang2, Tuo Hu2
1Department of Oncology Science, University of Oklahoma Health Campus, 940 Stanton L. Young Blvd., BMSB 332, Oklahoma City, OK, 73104, USA.
Abstract:
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.
Insights
Pancreatic cancer suppresses natural killer (NK) cells via myeloid cells that overexpress Apolipoprotein E (ApoE). Inhibiting lipid metabolism in these myeloid cells restores NK cell function, crucial for immunotherapy.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Natural killer (NK) cells are vital for cancer immunosurveillance and immunotherapy, particularly for pancreatic ductal adenocarcinomas (PDAC).
- Systemic immune changes accompany cancer, but PDAC's impact on systemic NK cells is unclear.
Purpose of the Study:
- To investigate how PDAC tumor burden affects systemic NK cell frequency and function.
- To identify mechanisms underlying NK cell suppression in PDAC.
Main Methods:
- Analysis of NK cell frequency and function in spleens of PDAC-bearing mice.
- Identification and characterization of splenic myeloid cell populations.
- Investigating the role of Apolipoprotein E (ApoE) in myeloid cell-mediated NK cell suppression.
- Genetic knockout of Apoe and treatment with lipid metabolism inhibitors.
Main Results:
- PDAC tumor burden decreased NK cell frequency and function in spleens.
- Increased Gr-1+ myeloid cells in spleens suppressed NK cell activity.
- Upregulated ApoE in myeloid cells promoted lipid oxidation and reactive oxygen species (ROS) generation, impairing NK cells.
- ApoE knockout or lipid metabolism inhibition restored NK cell function.
Conclusions:
- PDAC tumor burden induces systemic immune perturbations, specifically suppressing NK cells via myeloid cell-derived ApoE.
- Targeting lipid metabolism in myeloid cells can restore NK cell function.
- Understanding these systemic alterations is critical for effective NK cell-based PDAC immunotherapy.
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