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TGF-β-activated NK-92 cell therapy for esophageal squamous cell carcinoma
Hongyan Zhang1, Mengxing Guo2, Yujia Zhai1
1Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Abstract:
Esophageal squamous cell carcinoma (ESCC) is the dominant histological type of esophageal cancer in China, with a poor outcome and limited treatment options. The cytotoxicity of natural killer (NK) cells, independent of specific antigen recognition, renders them a promising candidate for cell-based immunotherapy of cancers. However, immunosuppressive cytokines, particularly TGF-β, are highly expressed in the ESCC tumor microenvironment and exert strong inhibitory effects on NK cells. To address this challenge, we genetically modified a well-established human NK cell line, NK-92, to express extracellular and transmembrane domains of the TGF-β receptor 2 along with 4-1BB costimulatory domain and CD3ζ (namely T4z chimeric receptor). NK-92 cells expressing T4z receptor (NK-92-T4z cells) were resistant to TGF-β-mediated suppressive signaling and even upregulated expression of NKG2D and perforin. Notably, NK-92-T4z cells showed higher oxidative phosphorylation and glycolytic activity in the presence of TGF-β. More importantly, NK-92-T4z cells displayed stronger cytotoxic activity against human ESCC cell lines in vitro, especially in a TGF-β-rich environment. Finally, adoptive transfer of NK-92-T4z cells reduced tumor growth in a xenograft ESCC model. These data suggest that converting inhibitory TGF-β signals to activating signals in NK cells may represent a valuable therapeutic strategy for patients with ESCC.
Insights
Genetically modified natural killer (NK) cells resist TGF-β suppression in esophageal squamous cell carcinoma (ESCC). These enhanced NK-92-T4z cells show improved cytotoxicity and reduce ESCC tumor growth, offering a promising immunotherapy strategy.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer death in China with limited therapies.
- Natural killer (NK) cells are promising for cancer immunotherapy due to their innate cytotoxic potential.
- The tumor microenvironment in ESCC highly expresses TGF-β, which suppresses NK cell function.
Purpose of the Study:
- To engineer NK-92 cells to overcome TGF-β-mediated immunosuppression in ESCC.
- To evaluate the efficacy of engineered NK-92 cells (NK-92-T4z) in vitro and in vivo.
Main Methods:
- Genetic modification of NK-92 cells to express a T4z chimeric receptor targeting TGF-β signaling.
- Assessment of NK-92-T4z cell resistance to TGF-β, functional marker expression, metabolic activity, and cytotoxicity against ESCC cell lines.
- Evaluation of NK-92-T4z cell efficacy in an ESCC xenograft mouse model.
Main Results:
- NK-92-T4z cells demonstrated resistance to TGF-β-induced suppression, with upregulated NKG2D and perforin.
- Engineered NK cells exhibited enhanced metabolic activity (oxidative phosphorylation and glycolysis) under TGF-β influence.
- NK-92-T4z cells displayed superior in vitro cytotoxicity against ESCC cells, particularly in TGF-β-rich conditions.
- Adoptive transfer of NK-92-T4z cells significantly inhibited tumor growth in a xenograft ESCC model.
Conclusions:
- Engineering NK cells to convert inhibitory TGF-β signals into activating signals is a viable strategy for ESCC immunotherapy.
- The T4z chimeric receptor enhances NK cell function and overcomes the immunosuppressive tumor microenvironment in ESCC.
- This approach holds potential as a novel therapeutic avenue for patients with esophageal squamous cell carcinoma.
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