Systemic immunosuppression limits NK cell therapy efficacy in pancreatic cancer
Recommended Citation
He C, Wang D, Hu T, Gonzalez D, Thakur R, Matysniak DP, King RJ, Kollala SS, Markov SD, Fujii Y, Tej G, Zhao J, Jin L, Oberley-Deegan R, Shukla SK, Zhang XA, Friedman JE, Singh PK, Hollingsworth MA, di Magliano MP, Crawford HC, Mehla K. Systemic Immunosuppression Limits Nk Cell Therapy Efficacy in Pancreatic Cancer. Mol Cancer. 2026;25(1).
Document Type
Article
Publication Date
7-8-2026
Publication Title
Molecular cancer [electronic resource]
Keywords
Animals, Killer Cells, Natural, Pancreatic Neoplasms, Humans, Mice, Tumor Microenvironment, Apolipoproteins E, Reactive Oxygen Species, Immunosuppression Therapy, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Disease Models, Animal, Immunotherapy, Lipid Metabolism
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.
Medical Subject Headings
Animals; Killer Cells, Natural; Pancreatic Neoplasms; Humans; Mice; Tumor Microenvironment; Apolipoproteins E; Reactive Oxygen Species; Immunosuppression Therapy; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Disease Models, Animal; Immunotherapy; Lipid Metabolism
PubMed ID
42421015
Volume
25
Issue
1
