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Immunotherapy

Avoiding CAR-NK cell fratricide

Nature Cancer volume 3, page 1445 (2022)Cite this article

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Trogocytosis is the transfer of a surface antigen from a target cell to a receptor on an effector cell at the immunological synapse. Trogocytosis occurs between tumor cells and chimeric antigen receptor (CAR)-expressing T cells, and it is known to regulate natural killer cell (NK cell) activity. In a study in Nature Medicine, Li et al. showed that activating CAR (aCAR)-expressing NK cells acquired surface expression of their cognate antigen via trogocytosis, and the presence of the trogocytic antigen (TROG) resulted in recognition and killing (‘fratricide’) by other aCAR-NK cells. Fratricide was reduced when aCAR-NK cells also expressed an inhibitory CAR (iCAR) (AI-CAR-NK cells) that, after recognition of an NK cell–specific self antigen, induced inhibitory signaling that dampened NK cell cytotoxicity.

CAR activation was required for effective trogocytosis, and an increasing number of TROG+ NK cells corresponded to a progressive reduction in TROG expression on the surface of target tumor cells, which is a hallmark of diminished susceptibility to CAR therapy. TROG+ NK cells that escaped fratricide presented a phenotype of functional exhaustion and metabolic dysregulation consistent with repeated TROG-induced CAR activation and self-engagement. In in vivo tumor mouse models, 80% of aCAR-NK cells were TROG+ by 20 days after injection, and the viability and persistence of aCAR-NK cells were reduced owing to fratricide and exhaustion, resulting in tumor-control failure. Furthermore, in participants in a CAR-NK cell trial, high blood levels of TROG+ CAR-NK cells were associated with recurrence.

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  1. Nature Cancer https://www.nature.com/natcancer

    Lucia Brunello

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  1. Lucia Brunello
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Correspondence to Lucia Brunello.

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Brunello, L. Avoiding CAR-NK cell fratricide. Nat Cancer 3, 1445 (2022). https://doi.org/10.1038/s43018-022-00476-w

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