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Targeting Cyclin D-CDK4/6 Sensitizes Immune-Refractory Cancer by Blocking the SCP3-NANOG Axis
Se Jin Oh1,2,3, Hanbyoul Cho4,5,6, Suhyun Kim7
1Laboratory of Tumor Immunology, Department of Biomedical Sciences, Graduate School of Medicine, Korea University, Seoul, Korea.
Abstract:
Immunoediting caused by antitumor immunity drives tumor cells to acquire refractory phenotypes. We demonstrated previously that tumor antigen-specific T cells edit these cells such that they become resistant to CTL killing and enrich NANOGhigh cancer stem cell-like cells. In this study, we show that synaptonemal complex protein 3 (SCP3), a member of the Cor1 family, is overexpressed in immunoedited cells and upregulates NANOG by hyperactivating the cyclin D1-CDK4/6 axis. The SCP3-cyclin D1-CDK4/6 axis was preserved across various types of human cancer and correlated negatively with progression-free survival of cervical cancer patients. Targeting CDK4/6 with the inhibitor palbociclib reversed multiaggressive phenotypes of SCP3high immunoedited tumor cells and led to long-term control of the disease. Collectively, our findings establish a firm molecular link of multiaggressiveness among SCP3, NANOG, cyclin D1, and CDK4/6 and identify CDK4/6 inhibitors as actionable drugs for controlling SCP3high immune-refractory cancer.Significance: These findings reveal cyclin D1-CDK4/6 inhibition as an effective strategy for controlling SCP3high immune-refractroy cancer. Cancer Res; 78(10); 2638-53. ©2018 AACR.
Insights
Tumor cells become resistant to immune attack by upregulating synaptonemal complex protein 3 (SCP3), which drives cancer stem cell growth. Inhibiting the cyclin D1-CDK4/6 pathway with drugs like palbociclib effectively controls this immune-refractory cancer.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Oncology
Background:
- Antitumor immunity can lead to tumor cells developing resistance to immune responses.
- Previous work showed T cells edit tumor cells, making them resistant to CTL killing and enriching NANOG-high cancer stem cells.
Purpose of the Study:
- To investigate the role of synaptonemal complex protein 3 (SCP3) in immunoedited cancer cells.
- To identify molecular mechanisms linking immunoediting, cancer stemness, and therapeutic resistance.
- To evaluate CDK4/6 inhibitors as a treatment strategy for SCP3-high immune-refractory cancers.
Main Methods:
- Analysis of SCP3 expression in immunoedited cells.
- Investigation of the SCP3-NANOG interaction and its effect on the cyclin D1-CDK4/6 axis.
- Assessment of the correlation between the SCP3-cyclin D1-CDK4/6 axis and patient survival.
- Treatment of SCP3-high immunoedited tumor cells with the CDK4/6 inhibitor palbociclib.
Main Results:
- SCP3 is overexpressed in immunoedited cells and upregulates NANOG by activating the cyclin D1-CDK4/6 axis.
- This axis is conserved across human cancers and linked to poorer progression-free survival in cervical cancer patients.
- Targeting CDK4/6 with palbociclib reversed aggressive phenotypes in SCP3-high cells and achieved long-term disease control.
Conclusions:
- A molecular link exists between SCP3, NANOG, cyclin D1, and CDK4/6 in driving cancer aggressiveness and immune refractoriness.
- CDK4/6 inhibitors represent a promising therapeutic strategy for SCP3-high immune-refractory cancers.
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