Targeting Cyclin D-CDK4/6 sensitizes immune-refractory cancer by blocking the SCP3-NANOG axis

Immune editing caused by anti-tumor 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 (CSC-like) cells. In the current study, we show that synaptonemal complex protein 3 (SCP3), a member of the Cor1 family, is overexpressed in immune-edited 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 multi-aggressive phenotypes of SCP3high immune-edited tumor cells and led to long-term control of the disease. Collectively, our findings establish a firm molecular link of multi-aggressiveness among SCP3, NANOG, Cyclin D1, and CDK4/6 and identify CDK4/6 inhibitors as actionable drugs for controlling SCP3high immune-refractory cancer.

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