抗原经历历史决定 CD8+ CAR-T 细胞在抗白血病应答中的不同功能状态

Chimeric antigen receptor T cells are an effective therapy for B-lineage malignancies.

However, many patients relapse and this therapeutic has yet to show strong efficacy in other hematologic or solid tumors. One opportunity for improvement lies in the ability to generate T cells with desirable functional characteristics.

Here, we dissect the biology of CD8+ CAR T cells (CAR8) by controlling whether the T cell has encountered cognate TCR antigen prior to CAR generation.

We find that prior antigen experience influences multiple aspects of in vitro and in vivo CAR8 functionality, resulting in superior effector function and leukemia clearance in the setting of limiting target antigen density compared to antigen-inexperienced T cells.

However, this comes at the expense of inferior proliferative capacity, susceptibility to phenotypic exhaustion and dysfunction, and inability to clear wildtype leukemia in the setting of limiting CAR+ cell dose.

Epigenomic and transcriptomic comparisons of these cell populations identified overexpression of the Runx2 transcription factor as a novel strategy to enhance CAR8 function, with a differential impact depending on prior cell state. Collectively, our data demonstrate that prior antigen experience determines functional attributes of a CAR T cell, as well as amenability to functional enhancement by transcription factor modulation.