Development of Novel NKp46-based Chimeric Antigen Receptors for Cancer Immunotherapy

Author(s): Bo Zou, Siqiang Lai, Meiyan Xu, Lin Qi, Wenyan Xu, Mingshu Han, Xiaohua Tan, Xingding Zhang, Qibin Liao

Chimeric antigen receptor (CAR)-T cell therapy has been highly successful in the treatment of hematological malignancies, yet its effectiveness in solid tumors remains limited. To develop CAR-T cell therapy for solid tumors, identifying new target antigens is crucial. NKp46, a critical natural cytotoxicity receptors (NCRs) on NK cells, play a pivotal role in their antitumor function. Interaction between NKp46 and its ligands activates NK cells, prompting the release of antitumor effector molecules. We found that NKp46 ligands (NKp46L) were specifically expressed in various tumor cells but absent in normal tissue cells, warranting further investigation. Consequently, we have developed novel second-generation CAR constructs featuring NKp46 extracellular immunoglobulin-like structural domains and demonstrated their in vitro cytotoxic activities against tumor cells. In conclusion, NKp46-based chimeric antigen receptors show promise in cancer immunotherapy but require further explorations.

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