Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia.
Faculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia.
Int J Mol Sci. 2023 Oct 13;24(20):15134. doi: 10.3390/ijms242015134.
TCR-like chimeric antigen receptor (CAR-T) cell therapy has emerged as a game-changing strategy in cancer immunotherapy, offering a broad spectrum of potential antigen targets, particularly in solid tumors containing intracellular antigens. In this study, we investigated the cytotoxicity and functional attributes of in vitro-generated T-lymphocytes, engineered with a TCR-like CAR receptor precisely targeting the cancer testis antigen MAGE-A4. Through viral transduction, T-cells were genetically modified to express the TCR-like CAR receptor and co-cultured with MAGE-A4-expressing tumor cells. Flow cytometry analysis revealed a significant surge in cells expressing activation markers CD69, CD107a, and FasL upon encountering tumor cells, indicating robust T-cell activation and cytotoxicity. Moreover, immune transcriptome profiling unveiled heightened expression of pivotal T-effector genes involved in immune response and cell proliferation regulation. Additionally, multiplex assays also revealed increased cytokine production and cytotoxicity driven by granzymes and soluble Fas ligand (sFasL), suggesting enhanced anti-tumor immune responses. Preliminary in vivo investigations revealed a significant deceleration in tumor growth, highlighting the therapeutic potential of these TCR-like CAR-T cells. Further investigations are warranted to validate these revelations fully and harness the complete potential of TCR-like CAR-T cells in overcoming cancer's resilient defenses.
T 细胞受体样嵌合抗原受体 (CAR-T) 细胞疗法在癌症免疫疗法中崭露头角，为治疗癌症提供了广泛的潜在抗原靶点，特别是在含有细胞内抗原的实体瘤中。在这项研究中，我们研究了体外生成的 T 淋巴细胞的细胞毒性和功能特性，这些 T 淋巴细胞经过基因工程改造，表达了针对癌症睾丸抗原 MAGE-A4 的 TCR 样 CAR 受体。通过病毒转导，T 细胞被遗传修饰以表达 TCR 样 CAR 受体，并与表达 MAGE-A4 的肿瘤细胞共培养。流式细胞术分析显示，当遇到肿瘤细胞时，表达激活标志物 CD69、CD107a 和 FasL 的细胞显著增加，表明 T 细胞的强烈激活和细胞毒性。此外，免疫转录组谱分析揭示了与免疫反应和细胞增殖调节相关的关键 T 效应基因的高表达。此外，多重分析还揭示了由颗粒酶和可溶性 Fas 配体 (sFasL) 驱动的细胞因子产生和细胞毒性的增加，表明增强了抗肿瘤免疫反应。初步的体内研究表明，肿瘤生长明显减缓，突显了这些 TCR 样 CAR-T 细胞的治疗潜力。需要进一步的研究来充分验证这些发现，并利用 TCR 样 CAR-T 细胞的全部潜力来克服癌症的弹性防御。
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