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Co-expression of IL-15 and CCL21 strengthens CAR-NK cells to eliminate tumors in concert with T cells and equips them with enhanced PI3K/AKT/mTOR signal signature

ABSTRACT: Chimeric antigen receptor (CAR) natural killer (NK) cell therapy has demonstrated safety and feasibility in clinic; yet, limited efficacy resulted from intrinsic dysfunction and extrinsic depression remains to be addressed. T cells provide a multifaceted complementation to NK cell-mediated response. Here, we designed a novel CD19-targeted CAR-NK armored with secreted interleukin (IL) -15 and CCL21 (15x21 CAR-NK) that are capable of recruiting and cooperating with T cells. These 15x21 CAR-NK cells possess excellent capacities for cytotoxicity, cytokine production, and effector molecule expression in vitro. The cooperation with T cells presents benefits of alleviating mutual exhaustion and boosting the expression of effector molecules/receptors, thus promoting the elimination of tumor cells efficiently. In addition, 15x21 CAR-NK cells were also highly enriched PI3K/AKT/mTOR pathway, associating with downstream pro-survival signaling, anti-apoptosis ability, and mitochondrial fitness. Collectively, our study highlights the intrinsic superiority and extrinsic T-cell cooperative advantages of 15x21 CAR-NK cells, providing a promising strategy for NK-cell based immunotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE278506 | GEO | 2025/04/25

REPOSITORIES: GEO

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