CAR-T 细胞设计依赖的脑肿瘤免疫微环境重塑鉴定巨噬细胞为抑制或促进抗肿瘤活性的关键参与者

Understanding interactions between adoptively transferred immune cells and the tumor immune microenvironment (TIME) is critical for developing successful T-cell based immunotherapies.

Here we investigated the impact of the TIME and chimeric antigen receptor (CAR) design on anti-glioma activity of B7-H3-specific CAR T-cells.

We show that five out of six B7-H3 CARs with varying transmembrane, co-stimulatory, and activation domains, exhibit robust functionality in vitro .

However, in an immunocompetent glioma model, these CAR T-cells demonstrated significantly varied levels of anti-tumor activity.

We used single-cell RNA sequencing to examine the brain TIME after CAR T-cell therapy.

We show that the TIME composition was influenced by CAR T-cell treatment.

We also found that successful anti-tumor responses were supported by the presence and activity of macrophages and endogenous T-cells.

Together, our study demonstrates that efficacy of CAR T-cell therapy in high-grade glioma is dependent on CAR structural design and its capacity to modulate the TIME.