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CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape

ABSTRACT: Chimeric antigen receptors (CARs) are synthetic receptors for antigen that reprogram T cell specificity, function and persistence. Patient-derived CAR T cells have demonstrated remarkable efficacy against a range of B-cell malignancies, and early trial results suggest activity in multiple myeloma. Despite high complete response rates, relapses occur in a large fraction of patients, some of which are antigen-negative and others antigen-low. Unlike mechanisms resulting in complete and permanent antigen loss, those leading to antigen-low tumour escape remain obscure. In murine leukaemia models, we show that CARs provoke reversible antigen loss through trogocytosis, an active process whereby target antigen is transferred to T cells, thereby decreasing target density on tumour cells and abating T cell activity by promoting fratricide killing and exhaustion. These mechanisms affect both CD28 and 4-1BB-based CARs, albeit differentially, depending on antigen density. They can be offset by cooperative killing and combinatorial targeting.

OTHER RELATED OMICS DATASETS IN: PXD012833

ORGANISM(S): Homo sapiens

PROVIDER: GSE126753 | GEO | 2019/03/27

REPOSITORIES: GEO

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CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape

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