Depletion of the RNA-Editing Enzyme ADAR1 Invigorates the Antitumor Immunity of NK Cells

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Natural killer (NK) cell immunotherapy shows promise but is limited by functional exhaustion and poor tumor infiltration.
• Adenosine deaminase acting on RNA 1 (ADAR1) is implicated in immunity and cancer, but its specific role in NK cells is unclear.

Purpose of the Study:

• To investigate the role of ADAR1 in NK cell function and its potential as a therapeutic target in cancer immunotherapy.

Main Methods:

• Assessed ADAR1 expression in peripheral blood NK cells from melanoma patients.
• Utilized ADAR1 knockdown and conditional knockout mouse models (Ncr1^iCre/+;ADAR1^flox/flox) to evaluate NK cell antitumor activity.
• Performed RNA sequencing (RNA-seq) on ADAR1-knockdown NK cells.
• Conducted 3D Matrigel-spheroid experiments to assess NK cell tumor infiltration.

Main Results:

• Elevated ADAR1 levels in melanoma patient NK cells correlated with impaired tumor killing.
• ADAR1 knockdown in NK cells enhanced antitumor activity in vitro and in vivo.
• ADAR1-deficient NK cells showed increased infiltration into tumors in conditional knockout mice.
• RNA-seq revealed an activated phenotype with enhanced migration potential in ADAR1-knockdown NK cells.
• ADAR1 deficiency led to decreased CD38 expression, boosting NK cell mobility, proliferation, and tumor-killing capacity.

Conclusions:

• ADAR1 negatively regulates NK cell antitumor functions, including infiltration and killing capacity.
• Downregulating ADAR1 in NK cells represents a viable strategy to improve cancer immunotherapy outcomes.
• ADAR1 is identified as a novel therapeutic target for enhancing NK cell-based cancer treatments.