OR7A10 GPCR engineering boosts CAR-NK therapy against solid tumours.

Area of Science:

• Immunology
• Oncology
• Cell Therapy

Background:

• Chimeric antigen receptor (CAR)-natural killer (NK) cell therapies show potential for solid tumors.
• Current limitations include poor tumor infiltration, persistence, and resistance within the tumor microenvironment.

Purpose of the Study:

• To identify gain-of-function targets for enhancing CAR-NK cell efficacy in solid tumors.
• To validate the therapeutic potential of identified targets through in vivo studies.

Main Methods:

• Unbiased in vivo CRISPR activation screen followed by a barcoded targeted in vivo open reading frame screen in primary human CAR-NK cells.
• Engineering CAR-NK cells with OR7A10 cDNA for functional assessment.
• Evaluation of engineered CAR-NK cell performance in solid tumor models.

Main Results:

• OR7A10, a G protein-coupled receptor (GPCR), was identified as a top candidate for enhancing CAR-NK cell function.
• OR7A10 engineering significantly improved CAR-NK cell proliferation, activation, cytotoxicity, persistence, and resistance to the tumor microenvironment.
• Reduced exhaustion was observed in OR7A10-engineered primary human NK cells.
• OR7A10-engineered CAR-NK cells demonstrated strong in vivo efficacy, achieving 100% complete response in an orthotopic breast cancer model.

Conclusions:

• OR7A10 is a potent gain-of-function target for improving CAR-NK cell therapy for solid tumors.
• OR7A10-engineered CAR-NK cells represent a promising, scalable, off-the-shelf therapeutic strategy for solid tumor treatment.