Alsalloum Alaa, Alrhmoun Saleh, Shevchenko Julia, Fisher Marina, Philippova Julia, Perik-Zavodskii Roman, Perik-Zavodskaia Olga, Lopatnikova Julia, Kurilin Vasily, Volynets Marina, Akahori Yasushi, Shiku Hiroshi, Silkov Alexander, Sennikov Sergey
Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk 630099, Russia.
Faculty of Natural Sciences, Novosibirsk State University, Novosibirsk 630090, Russia.
Biomedicines. 2023 Oct 16;11(10):2805. doi: 10.3390/biomedicines11102805.
Adoptive T-cell therapies tailored for the treatment of solid tumors encounter intricate challenges, necessitating the meticulous selection of specific target antigens and the engineering of highly specific T-cell receptors (TCRs). This study delves into the cytotoxicity and functional characteristics of in vitro-cultured T-lymphocytes, equipped with a TCR designed to precisely target the cancer-testis antigen NY-ESO-1. Flow cytometry analysis unveiled a notable increase in the population of cells expressing activation markers upon encountering the NY-ESO-1-positive tumor cell line, SK-Mel-37. Employing the NanoString platform, immune transcriptome profiling revealed the upregulation of genes enriched in Gene Ontology Biological Processes associated with the IFN-γ signaling pathway, regulation of T-cell activation, and proliferation. Furthermore, the modified T cells exhibited robust cytotoxicity in an antigen-dependent manner, as confirmed by the LDH assay results. Multiplex immunoassays, including LEGENDplex™, additionally demonstrated the elevated production of cytotoxicity-associated cytokines driven by granzymes and soluble Fas ligand (sFasL). Our findings underscore the specific targeting potential of engineered TCR T cells against NY-ESO-1-positive tumors. Further comprehensive in vivo investigations are essential to thoroughly validate these results and effectively harness the intrinsic potential of genetically engineered T cells for combating cancer.
为治疗实体瘤量身定制的过继性T细胞疗法面临着复杂的挑战，这就需要精心挑选特定的靶抗原，并设计高度特异性的T细胞受体（TCR）。本研究深入探讨了体外培养的T淋巴细胞的细胞毒性和功能特性，这些T淋巴细胞配备了一种旨在精确靶向癌-睾丸抗原NY-ESO-1的TCR。流式细胞术分析显示，在遇到NY-ESO-1阳性肿瘤细胞系SK-Mel-37时，表达激活标志物的细胞群体显著增加。利用NanoString平台进行的免疫转录组分析揭示了在与IFN-γ信号通路、T细胞激活调节和增殖相关的基因本体生物学过程中富集的基因上调。此外，如乳酸脱氢酶（LDH）检测结果所证实，修饰后的T细胞以抗原依赖的方式表现出强大的细胞毒性。包括LEGENDplex™在内的多重免疫分析还表明，由颗粒酶和可溶性Fas配体（sFasL）驱动的细胞毒性相关细胞因子的产生增加。我们的研究结果强调了工程化TCR T细胞对NY-ESO-1阳性肿瘤的特异性靶向潜力。进一步全面的体内研究对于彻底验证这些结果并有效利用基因工程T细胞对抗癌症的内在潜力至关重要。
