ADAR1 expression is associated with cervical cancer progression and negatively regulates NK cell activity

Valentina Tassinari & Alessandra Soriani et al. · 2025-07-08

1Citations
ADAR1 edits double-stranded RNAs (dsRNAs) by deaminating adenosines into inosines, preventing aberrant activation of innate immunity by endogenous dsRNAs, which may resemble viral structures. Several tumors exploit ADAR1 to evade immune surveillance; indeed, its deletion reduces tumor viability and reshapes infiltrating leukocytes. Here we investigated the role of ADAR1 in immune evasion mechanisms during cervical cancer (CC) progression. Patients' biopsy samples showed higher ADAR1 expression already in premalignant lesions (squamous intraepithelial lesions [SIL]) and a substantially reduced percentage of infiltrating CD7+ innate cells in in situ and invasive carcinomas compared with normal mucosa, with CD56+ NK cells showing phenotypic alterations that may have affected their functional responses. In CC-derived cell lines (SiHa, CaSki), ADAR1 silencing reduced cell proliferation, an effect further enhanced by exogenous IFN-β administration. It also induced proinflammatory gene expression, as demonstrated by RNA-Seq analysis, and conditioned supernatants collected from these cells activated several NK cell effector functions. NK cell infiltration and activation were also confirmed in organotypic 3D tissue models of SiHa cells knocked out for ADAR1. In conclusion, ADAR1 expression increased with CC progression and was accompanied by alterations in tumor-infiltrating NK cells, but its silencing in CC-derived cell lines potentiated antitumor NK cell activities. Thus, ADAR1 inhibition may represent a therapeutic perspective for CC and possibly other malignancies.
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DOIPubMed
Journal
JCI Insight
TL;DR

ADAR1 expression increased with CC progression and was accompanied by alterations in tumor-infiltrating NK cells, but its silencing in CC-derived cell lines potentiated antitumor NK cell activities, suggesting ADAR1 inhibition may represent a therapeutic perspective for CC and possibly other malignancies.

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Authors
Valentina Tassinari, Marta Kaciulis, Stefano Petrai, Helena Stabile, Angelina Pernazza, Martina Leopizzi, Valeria Di Maio, Francesca Belleudi, Danilo Ranieri, Vanessa Mancini, Innocenza Palaia, Federica Tanzi, Ludovica Lospinoso Severini, Silvia Ruggeri, Maria Emanuela Greco, Giovanni Bernardini, Alessandra Zingoni, Marco Cippitelli, Cristina Cerboni, Alessandra Soriani
Funding
AIRC Grant ID 25680Institut Pasteur Grant PTR Project 432-21Ministry of University and Research Grant Prot. 2022S3AZCCNextGenerationEU through the Italian Ministry of University and Research under PNRR—M4C2-I1.3 Grant Project PE_00000019 “HEAL ITALIA”Ministry of University and Research Grant Prot. 20223RRASSSapienza University of Rome-Progetto di Ricerca 2022- Grant RG123188A3D8C26E