ADAR1 expression is associated with cervical cancer progression and negatively regulates NK cell activity
Valentina Tassinari1, Marta Kaciulis1, Stefano Petrai1
1Department of Molecular Medicine.
Abstract:
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.
Insights
Adenosine deaminase acting on RNA 1 (ADAR1) promotes cervical cancer immune evasion by altering NK cell function. Inhibiting ADAR1 may enhance anti-tumor immunity, offering a potential therapeutic strategy for cervical cancer.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Adenosine deaminase acting on RNA 1 (ADAR1) modifies double-stranded RNAs (dsRNAs), preventing innate immune activation by endogenous dsRNAs that mimic viral structures.
- Tumors utilize ADAR1 for immune evasion, with its deletion impacting tumor viability and leukocyte infiltration.
- Cervical cancer (CC) progression involves complex immune evasion mechanisms.
Purpose of the Study:
- To investigate the role of ADAR1 in immune evasion during cervical cancer progression.
- To assess the impact of ADAR1 on tumor-infiltrating immune cells, particularly Natural Killer (NK) cells.
- To explore the therapeutic potential of ADAR1 inhibition in cervical cancer.
Main Methods:
- Analysis of ADAR1 expression in human cervical cancer biopsy samples, including premalignant lesions.
- Flow cytometry to evaluate infiltrating immune cells (CD7+, CD56+ NK cells) in tumor tissues.
- ADAR1 silencing in cervical cancer cell lines (SiHa, CaSki) followed by proliferation assays, RNA-Seq, and NK cell functional assays.
- Organotypic 3D tissue models were used to confirm NK cell infiltration and activation upon ADAR1 knockout.
Main Results:
- Elevated ADAR1 expression was observed in cervical cancer and premalignant lesions compared to normal mucosa.
- A decrease in CD7+ innate cells and altered CD56+ NK cell phenotypes were noted in invasive carcinomas.
- ADAR1 silencing in CC cell lines reduced proliferation, enhanced proinflammatory gene expression, and boosted NK cell effector functions.
- NK cell infiltration and activation were confirmed in ADAR1-knockout 3D models.
Conclusions:
- ADAR1 expression increases with cervical cancer progression, correlating with altered tumor-infiltrating NK cell populations.
- Silencing ADAR1 in cervical cancer cells potentiates anti-tumor NK cell activities.
- ADAR1 inhibition presents a promising therapeutic strategy for cervical cancer and potentially other malignancies.
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