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KIR-based inhibition of CARs overcame CAR-NK cell division-mediated cannibalism and tumor escape

 Last Update: 2022-10-14
 Source: Internet
 Author: User

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Trogocytosis is an active process
that transfers surface material from target cells to effector cells.
Using multiple in vivo tumor models and clinical data, we report that chimeric antigen receptor (CAR) activation in natural killer (NK) cells promotes the transfer of CAR homologous antigens from tumors to NK cells, resulting in (1) decreased tumor antigen density, thereby impairing the ability of CAR-NK cells to bind to their target cells, and (2) inducing self-recognition and CAR-mediated sustained involvement, leading to cannibalism and NK cell hypoactivity of NK cells expressing trophoblast antigens
。 This phenomenon can be counteracted by a dual CAR system that combines an activated CAR against homologous tumor antigens and an NK self-identifying inhibitory CAR that transmits a "don't kill me" signal to NK cells when in contact with TROG+ sibling cells
.
This system prevents trophoblast antigen-mediated cannibalism while avoiding activation of CAR signaling against tumor antigens and leading to enhanced
CAR-NK cell activity.

KIR-based inhibitory CARs overcome CAR-NK cell trogocytosis-mediated fratricide and tumor escape

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