Decitabine Treatment Induces a Viral Mimicry Response in Cervical Cancer Cells and Further Sensitizes Cells to Chemotherapy.

Abstract

To investigate the anti-cancer, chemosensitizing and/or immunomodulating effects of decitabine (DAC) to be used as a potential therapeutic agent for the treatment of cervical cancer (CC). Cervical cancer cell lines were treated with low doses of DAC treatment used as a single agent or in combination with chemotherapy. End-point in vitro assays were developed as indicators of the anti-cancer and/or immunomodulating effects of DAC treatment in CC cells. These assays include cell viability, cell cycle analysis, apoptosis, induction of a viral-mimicry response pathway, expression of MHC-class I and PD-L1 and chemosensitivity. High and low doses of DAC treatment induced reduction in cell viability in HeLa (HPV18+), CaSki (HPV16+) and C33A (HPV-) cells. Specifically, a time-dependent reduction in cell viability of HeLa and CaSki cells was observed accompanied by robust cell cycle arrest at G2/M phase and alterations in the cell cycle distribution. Decrease in cell viability was also observed in a non-transformed immortal keratinocyte (HaCat) suggesting a non-cancer specific target effect. DAC treatment also triggered a viral mimicry response through long-term induction of cytoplasmic double-stranded RNA (dsRNA) and activation of downstream IFN-related genes in both HPV+ and HPV- cells. In addition, DAC treatment increased the number of CC cells expressing MHC-class I and PD-L1. Furthermore, DAC significantly increased the proportion of early and late apoptotic CC cells quantified using FACS. Our combination treatments showed that low dose DAC treatment sensitizes cells to chemotherapy. Low doses of DAC treatment promotes robust induction of a viral mimicry response, immunomodulating and chemosensitizing effects in CC, indicating its promising therapeutic role in CC in vitro.