Ricerc@Sapienza

Cervical cancer (CC) is the 4th most common cause of death from tumor in women worldwide, and virtually all CC are caused by sexually-transmitted high-risk human papilloma viruses (hrHPVs). In general, it takes 10 to 20 years for the premalignant condition to progress to cancer, reflecting the inability of host immunity to clear abnormal cells. Indeed, hrHPVs are notorious for their ability to evade immune responses and to avoid direct recognition of infected/transformed cells by cytotoxic lymphocytes. In addition, hrHPVs suppress type I IFN pathways, thus adding a further level of immunosuppression.
Among the cytosolic proteins regulating IFN-I production is ADAR1, an RNA editing enzyme that converts adenosines to inosines within double-stranded RNA, leading to diversification of both transcriptome and proteome landscapes. In most tumors, hyper-editing of RNA by elevated ADAR1 activity results in suppression of immunity, while ADAR1 ablation enhances activation of cytoplasmic innate immune sensors and IFN-signaling, resulting in reduced cancer cell viability.
Hence, our hypothesis is that ADAR1 plays a critical role in hrHPV-driven CC, through its ability to suppress IFN-I and immune responses mediated by innate lymphocytes. To address these issues, we will: 1) characterize ADAR1 expression in cervical biopsies from different groups of CC patients, and correlate it with disease stage and/or patient survival; 2) dissect the impact that ADAR1 manipulation has on IFN-I signaling pathways, pro-inflammatory cytokine production and innate lymphocyte-mediated immune responses (NK and ILCs).
We aim to identify novel mechanisms of immune suppression sustaining HPV-driven tumorigenesis and to characterize NK/ILC subsets endowed with distinct functional properties that can affect CC progression. We expect that our findings will pose the basis for future studies aiming at reactivating innate immunity via the delivery of small RNAs antagonizing ADAR1 and with anti-tumor effect.