嵌合抗原受体T（CAR-T）细胞在治疗实体肿瘤方面的疗效有限，这主要是由于抗原异质性和免疫抑制的肿瘤微环境（TME）所致。B7-H3在大多数实体肿瘤中过度表达，成为癌症治疗的有希望的靶点。本研究旨在探讨B7-H3-CAR-T联合放疗治疗实体瘤模型的效果。通过制备和测试辐照肿瘤细胞系，构建了人源化的B7-H3-CAR-T，并评估了B7-H3-CAR-T在体外和体内预处理放疗条件下对实体瘤模型的细胞毒性。结果发现，放疗可以显著增加胰腺癌（PANC-1）、结直肠癌（HCT-15、SW620）、急性髓细胞性白血病（AML-5）、表皮样癌（KB）和胶质瘤（U87-MG）人类细胞系中B7-H3的表达水平。6Gy放疗还发现可以上调结直肠癌细胞（HCT-15）中的肿瘤浸润分子，如细胞内黏附分子-1（ICAM-1）或FAS，支持放疗的可能协同增强效应。体外和体内实验证明，放疗确实显著增强了B7-H3-CAR-T浸润和杀伤肿瘤的能力。有趣的是，在双肿瘤小鼠模型研究中发现，不仅辐照侧的肿瘤细胞被完全消灭，辐照还增强了对非辐照侧的CAR-T肿瘤杀伤能力，证实了辐照与CAR-T治疗存在非局部效应。我们的结果表明，B7-H3-CAR-T联合放疗可能是治疗实体肿瘤的有希望的方法。版权所有 © 2023. Elsevier Inc. 发布。

Limited efficacy of chimeric antigen receptor T (CAR-T) cells in treating solid tumors is largely due to the antigen heterogeneity and immunosuppressive tumor microenvironment (TME). B7-H3 is over-expressed in most kind of solid tumors, making it a promising target for cancer treatment. This study aims to explore the effect of B7-H3-CAR-T therapy combined with radiotherapy in treating solid tumor models.Irradiated tumor cell lines were prepared and tested. A humanized B7-H3-CAR-T was constructed, and it was evaluated that B7-H3-CAR-T cytotoxicity against solid tumor models with preconditioning of radiotherapy in vitro and vivo.Irradiation was found to increase expression level of B7-H3 in pancreatic cancer (PANC-1), colorectal cancer (HCT-15, SW620), acute myelocytic leukemia (AML-5), epidermoid carcinoma (KB) and glioma (U87-MG) human cell lines significantly. 6Gy irradiation was also found to up-regulate tumor-infiltration molecule like intracellular adhesion molecule-1 ICAM-1 or FAS in HCT-15 cells, supporting a possible synergistic enhancement effect of radiotherapy. In vitro and in vivo experiments demonstrated that irradiation indeed significantly enhanced the ability of B7-H3-CAR-T to infiltrate and kill tumors. Interestingly in dual-tumor mouse model study, not only tumor cells on irradiation side were eradicated completely, irradiation also enhanced CAR-T tumor-killing ability on non-irradiated side, confirming the abscopal effect of irradiation existed with CAR-T therapy.Our results suggest that B7-H3-CAR-T therapy combined with radiotherapy may be a promising modality in treating solid tumors.Copyright © 2023. Published by Elsevier Inc.