ASK1 suppresses NK cell-mediated intravascular tumor cell clearance in lung metastasis
Makoto Fujimoto1, Miki Kamiyama1, Kosuke Fuse1
1Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Abstract:
Tumor metastasis is the leading cause of death worldwide and involves an extremely complex process composed of multiple steps. Our previous study demonstrated that apoptosis signal-regulating kinase 1 (ASK1) deficiency in mice attenuates tumor metastasis in an experimental lung metastasis model. However, the steps of tumor metastasis regulated by ASK1 remain unclear. Here, we showed that ASK1 deficiency in mice promotes natural killer (NK) cell-mediated intravascular tumor cell clearance in the initial hours of metastasis. In response to tumor inoculation, ASK1 deficiency upregulated immune response-related genes, including interferon-gamma (IFNγ). We also revealed that NK cells are required for these anti-metastatic phenotypes. ASK1 deficiency augmented cytokine production chemoattractive to NK cells possibly through induction of the ligand for NKG2D, a key activating receptor of NK cells, leading to further recruitment of NK cells into the lung. These results indicate that ASK1 negatively regulates NK cell-dependent anti-tumor immunity and that ASK1-targeted therapy can provide a new tool for cancer immunotherapy to overcome tumor metastasis.
Insights
Apoptosis signal-regulating kinase 1 (ASK1) deficiency enhances natural killer (NK) cell activity, reducing tumor metastasis. This finding suggests ASK1-targeted therapy could be a new cancer immunotherapy approach.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Oncology
Background:
- Tumor metastasis is a leading cause of cancer mortality.
- Apoptosis signal-regulating kinase 1 (ASK1) deficiency was previously shown to attenuate tumor metastasis.
- The precise mechanisms by which ASK1 influences metastasis remain largely unknown.
Purpose of the Study:
- To elucidate the role of ASK1 in regulating specific steps of tumor metastasis.
- To investigate the impact of ASK1 deficiency on immune cell activity during metastasis.
- To explore the potential of targeting ASK1 for cancer immunotherapy.
Main Methods:
- Utilized a mouse model of experimental lung metastasis.
- Analyzed gene expression related to immune responses in ASK1-deficient mice.
- Investigated the role of natural killer (NK) cells in anti-metastatic effects.
- Assessed cytokine production and NKG2D ligand expression.
Main Results:
- ASK1 deficiency promotes NK cell-mediated clearance of intravascular tumor cells.
- ASK1 deficiency upregulates immune response genes, including interferon-gamma (IFNγ).
- NK cells are essential for the anti-metastatic effects observed in ASK1-deficient mice.
- ASK1 deficiency enhances NK cell recruitment to the lungs via increased chemoattractant cytokines and NKG2D ligand induction.
Conclusions:
- ASK1 negatively regulates NK cell-dependent anti-tumor immunity.
- Targeting ASK1 may represent a novel strategy for cancer immunotherapy to combat tumor metastasis.
- Understanding ASK1's role in immune regulation opens new avenues for therapeutic intervention.
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