The pronounced cytotoxic effects of chimeric antigen receptor T cells targeting B7-H3 in organoids and liver xenografts derived from colorectal cancer patients.

IF 6.8 1区医学 Q1 ONCOLOGY

British Journal of Cancer Pub Date : 2025-07-28 DOI:10.1038/s41416-025-03114-1

Yuling Sheng, Li Yan, Qi Liu, Yifan Peng, Jingyun Tan, Wenhua Li, Wei Mao, Wenqing Wei, Yanyun Chang, Linlin Cao, Yi Tan, Yanlin Xiao, Wenyong Zhang, Jing Gao, Yang Xu, Changzheng Du

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引用次数: 0

Abstract

Background: The application of chimeric antigen receptor (CAR)-T cells in solid tumors is hindered due to the lack of specific tumor antigen and limited clinical efficacy. Our aim is to develop and validate novel CAR-T cell therapy against metastatic colorectal cancer (CRC).

Methods: By analyzing the expression of B7-H3 in CRC tissue and cell lines using immunohistochemistry (IHC) and flow cytometry, respectively, we identified B7-H3 as a potential target in CRC. We thereby developed CAR-T cells targeting B7-H3 (B7-H3 CAR-T) and evaluated their anti-tumor activity in vitro and in vivo, using patient-derived organoids (PDOs) and xenograft (PDX) models to validate its translational potential.

Results: In our cohort of 170 CRC patients, B7-H3 was significantly upregulated in CRC tumors compared to paratumor tissue, as determined by IHC staining. When co-cultured with CRC cells or PDOs, B7-H3 CAR-T cells exhibited a dose-dependent cytotoxicity in vitro. Furthermore, B7-H3 CAR-T cells effectively controlled tumor growth and metastasis in vivo, significantly prolonging survival time for the tumor-burden mice through cytotoxic killing and potential immune regulatory effects, demonstrated in both CRC cell-based and PDX-based metastatic models.

Conclusions: These findings underscore the potential efficacy of B7-H3 CAR-T cells for treating metastatic CRC and highlight its translational value.

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靶向B7-H3的嵌合抗原受体T细胞在结直肠癌患者的类器官和肝脏异种移植中显著的细胞毒性作用。

背景：由于缺乏特异性肿瘤抗原和临床疗效有限，CAR -T细胞在实体瘤中的应用受到阻碍。我们的目标是开发和验证针对转移性结直肠癌（CRC）的新型CAR-T细胞疗法。方法：利用免疫组织化学（IHC）和流式细胞术分别分析B7-H3在结直肠癌组织和细胞系中的表达，确定B7-H3是结直肠癌的潜在靶点。因此，我们开发了靶向B7-H3的CAR-T细胞（B7-H3 CAR-T），并在体外和体内评估了它们的抗肿瘤活性，使用患者来源的类器官（PDOs）和异种移植（PDX）模型来验证其转化潜力。结果：在我们的170例CRC患者队列中，通过免疫组化染色发现，与肿瘤旁组织相比，B7-H3在CRC肿瘤中显著上调。当与CRC细胞或PDOs共培养时，B7-H3 CAR-T细胞在体外表现出剂量依赖性的细胞毒性。此外，B7-H3 CAR-T细胞在体内有效地控制肿瘤生长和转移，通过细胞毒杀伤和潜在的免疫调节作用显著延长肿瘤负荷小鼠的生存时间，这在基于CRC细胞和基于pdx的转移模型中都得到了证实。结论：这些发现强调了B7-H3 CAR-T细胞治疗转移性结直肠癌的潜在疗效，并强调了其翻译价值。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

British Journal of Cancer 医学-肿瘤学

CiteScore

15.10

自引率

1.10%

发文量

383

审稿时长

6 months

期刊介绍： The British Journal of Cancer is one of the most-cited general cancer journals, publishing significant advances in translational and clinical cancer research.It also publishes high-quality reviews and thought-provoking comment on all aspects of cancer prevention,diagnosis and treatment.