Dottorato in INNOVATION IN IMMUNO-MEDIATED AND HEMATOLOGICAL DISORDERS

Titolo della tesi: Exploring the interplay between the RNA editing enzyme ADAR1 and innate immune responses in cervical cancer.

Development of cervical cancer (CC) is closely linked to persistent infection with HPVs, the most frequent sexually transmitted infectious agents worldwide. Though prophylactic vaccines are available, many people remain unvaccinated and the vaccine does not prevent cancer development in individuals who are already infected. Cancer progression can take 10 to 20 years, reflecting a long-lasting inability of immune responses to eliminate infected and abnormal cells, but also suggesting that there is an ample interval for therapeutic interventions. Among immune evasion mechanisms, ADAR1 may play a role since it senses endogenous double-stranded (ds) RNAs, which may resemble viral structures, and by editing adenosines into inosines, prevents aberrant activation of innate immune pathways (e.g., IFN-I production). In most cancer types, ADAR1 is overexpressed, as tumors exploit its IFN-suppressing activity and ability to edit genes, impacting oncogenes and tumor suppressors. In this project we addressed for the first time the possibility to restore innate immune responses against CC - in particular IFN-I and innate cytotoxic lymphocytes – by manipulating the expression of ADAR1. Our main observations were: i) an increased ADAR1 expression during CC progression; ii) the infiltration of innate lymphocytes (NK cells, ILCs), identified in cervix-derived fresh biopsies; iii) the penetration of NK cells also in 3D-organotypic raft cultures of CC cells; iv) an increased expression of IFN-I and several inflammatory chemokines/cytokines in ADAR1-silenced CC cell lines; v) a potent activation of NK cells treated with conditioned media of ADAR1-silenced cells. These findings suggest that inhibition of ADAR1 expression and/or editing might represent a therapeutic perspective for cervical and other cancers as well.