B7-H3 CAR-T 对肾细胞癌疗效的临床前评估。

IF 3.2 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular immunology Pub Date : 2024-11-07 DOI:10.1016/j.molimm.2024.10.006

Huizhong Li , Fei Wang , Haifang Zhao , Jiale Cao , Shiyuan Wang , Hongxia Li , Barbara Savoldo , Enyu Rao , Gianpietro Dotti , Hongwei Du

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引用次数: 0

摘要

B7-H3是一种I型跨膜蛋白，属于B7免疫检查点蛋白家族，在癌细胞中异常表达，但在正常组织中却很少表达，因此是一种有吸引力的癌症治疗靶点。在这里，我们发现 B7-H3 在肾细胞癌（RCC）肿瘤组织和 RCC 细胞系中高表达，但在正常肾组织中检测不到。因此，我们设计了靶向B7-H3的第二代CAR-T细胞，并加入了CD28或4-1BB共刺激结构域。这两种CAR-T细胞变体在体外、转移性和正位RCC小鼠模型中都显示出了对RCC肿瘤的强大抗肿瘤活性。此外，B7-H3 CAR-T 细胞在与 RCC 癌细胞共培养时表现出显著的增殖性和强大的细胞因子释放能力。这些研究结果表明，通过 CAR-T 细胞靶向 B7-H3 有可能为 RCC 患者提供一种新的治疗选择。

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Preclinical assessment of the efficacy of B7-H3 CAR-T in renal cell carcinoma

B7-H3 is a type I transmembrane protein that belongs to the B7 immune checkpoint protein family, is aberrantly expressed in cancer cells, but rarely expressed in normal tissues, making it an attractive target for cancer therapy. Here, we found B7-H3 is highly expressed in the renal cell carcinoma (RCC) tumor tissues and RCC cell lines, but is undetectable in normal renal tissues. Therefore, we engineered second-generation CAR-T cells targeting B7-H3, incorporating either CD28 or 4–1BB co-stimulatory domains. Both CAR-T cell variants demonstrated potent antitumor activity against RCC tumors in vitro and in metastatic and orthotopic RCC mouse models. Furthermore, the B7-H3 CAR-T cells exhibited remarkable proliferation and robust cytokine release when co-cultured with RCC cancer cells. These findings demonstrated that targeting B7-H3 by CAR-T cells potentially offering a new treatment option for RCC patients.

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来源期刊

Molecular immunology 医学-免疫学

CiteScore

6.90

自引率

2.80%

发文量

324

审稿时长

50 days

期刊介绍： Molecular Immunology publishes original articles, reviews and commentaries on all areas of immunology, with a particular focus on description of cellular, biochemical or genetic mechanisms underlying immunological phenomena. Studies on all model organisms, from invertebrates to humans, are suitable. Examples include, but are not restricted to: Infection, autoimmunity, transplantation, immunodeficiencies, inflammation and tumor immunology Mechanisms of induction, regulation and termination of innate and adaptive immunity Intercellular communication, cooperation and regulation Intracellular mechanisms of immunity (endocytosis, protein trafficking, pathogen recognition, antigen presentation, etc) Mechanisms of action of the cells and molecules of the immune system Structural analysis Development of the immune system Comparative immunology and evolution of the immune system "Omics" studies and bioinformatics Vaccines, biotechnology and therapeutic manipulation of the immune system (therapeutic antibodies, cytokines, cellular therapies, etc) Technical developments.

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