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地西他滨介导的卵巢癌细胞中CSPG4上调使得CSPG4特异性CAR-T细胞能够进行靶向治疗。

Decitabine-Mediated Upregulation of CSPG4 in Ovarian Carcinoma Cells Enables Targeting by CSPG4-Specific CAR-T Cells.

作者信息

Harrer Dennis Christoph, Schenkel Charlotte, Berking Carola, Herr Wolfgang, Abken Hinrich, Dörrie Jan, Schaft Niels

机构信息

Department of Hematology and Internal Oncology, University Hospital Regensburg, 93053 Regensburg, Germany.

Department of Dermatology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Hartmannstraße 14, 91052 Erlangen, Germany.

出版信息

Cancers (Basel). 2022 Oct 14;14(20):5033. doi: 10.3390/cancers14205033.

Abstract

The addition of CAR-T cells to the armamentarium of immunotherapy revigorated the field of oncology by inducing long-lasting remissions in patients with relapsing/refractory hematological malignancies. Nevertheless, in the lion's share of patients diagnosed with solid tumors, CAR-T-cell therapy so far failed to demonstrate satisfactory anti-tumor activity. A crucial cause of resistance against the antigen-specific attack of CAR-T cells is predicated on the primary or secondary absence of suitable target antigens. Thus, the necessity to create a broad repertoire of different target antigens is vital. We aimed to evaluate the potential of the well-established melanoma antigen chondroitin sulfate proteoglycan 4 (CSPG4) as an inducible antigen in ovarian cancer cells, using CSPG4-negative SKOV-3 ovarian cancer cells as a model. Based on the hypomethylating activity of the FDA-approved drug decitabine, we refined a protocol to upregulate CSPG4 in the majority of decitabine-treated SKOV-3 cells. CSPG4-specific CAR-T cells generated by mRNA-electroporation showed CSPG4-directed cytokine secretion and cytotoxicity towards decitabine-treated SKOV-3. Another ovarian cancer cell line (Caov-3) and the neoplastic cell line 293T behaved similar. In aggregate, we generated proof-of-concept data paving the way for the further exploration of CSPG4 as an inducible antigen for CAR-T cells in ovarian cancer.

摘要

将嵌合抗原受体T细胞(CAR-T细胞)添加到免疫治疗手段中,通过诱导复发/难治性血液系统恶性肿瘤患者实现长期缓解,为肿瘤学领域注入了新的活力。然而,在大多数被诊断为实体瘤的患者中,CAR-T细胞疗法目前未能展现出令人满意的抗肿瘤活性。对CAR-T细胞抗原特异性攻击产生抗性的一个关键原因在于原发性或继发性缺乏合适的靶抗原。因此,创建广泛多样的不同靶抗原至关重要。我们旨在以CSPG4阴性的SKOV-3卵巢癌细胞为模型,评估成熟的黑色素瘤抗原硫酸软骨素蛋白聚糖4(CSPG4)作为卵巢癌细胞中可诱导抗原的潜力。基于美国食品药品监督管理局(FDA)批准的药物地西他滨的低甲基化活性,我们完善了一种方案,以在大多数经地西他滨处理的SKOV-3细胞中上调CSPG4。通过mRNA电穿孔产生的CSPG4特异性CAR-T细胞表现出针对CSPG4的细胞因子分泌以及对经地西他滨处理的SKOV-3细胞的细胞毒性。另一种卵巢癌细胞系(Caov-3)和肿瘤细胞系293T表现相似。总体而言,我们生成了概念验证数据,为进一步探索CSPG4作为卵巢癌中CAR-T细胞的可诱导抗原铺平了道路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0de2/9599610/1fcb3226a3cc/cancers-14-05033-g001.jpg

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