嵌合抗原T细胞疗法(CAR-T)在治疗血液恶性肿瘤上取得了突破性进展【1】,但在实体瘤的应用中由于受肿瘤免疫抑制微环境的影响,导致CAR-T细胞增殖差、持久性低以及杀伤功能弱,使得传统CAR-T对实体瘤的临床治疗效果并不理想【2】。已有研究表明,GITR(Glucocorticoid-induced tumor necrosis factor receptor, 又称肿瘤坏死因子超家族成员18)及其配体GITRL (TNFSFL18) 作为近些年发现的与T细胞功能调节密切相关的新型共刺激分子,与经典的4-1BB共刺激信号及其招募的TRAF分子具有独特而又高度互补的调节作用。GITR/GITRL信号不仅能够增强T细胞的存活及增殖、诱导Th9细胞的分化,还能抑制Treg细胞的活性【3-6】。因此,GITR/GITRL信号独特的调控功能给CAR-T细胞疗法在实体肿瘤中治疗效果的提升带来了希望。 近日,华东师范大学杜冰教授团队在Molecular Therapy杂志上发表题为GITRL enhances cytotoxicity and persistence of CAR-T cells in cancer therapy的论文【7】,发现过表达GITRL的CAR-T细胞不仅可以直接增强CAR-T细胞的抗肿瘤活性,还可以促进其在实体肿瘤微环境中的持久性,进一步提高CAR-T对实体肿瘤的治疗效果。相较于传统PSMA-CAR-T,过表达GITRL的CAR-T细胞显著提升对前列腺癌细胞的杀伤能力。表明GITR/GITRL信号在促进CAR-T治疗实体瘤疗效上具有巨大潜力,为实体肿瘤的CAR-T治疗提供了一种新策略。
1. Park, J.H., Riviere, I., Gonen, M., Wang, X., Senechal, B., Curran, K.J., Sauter, C., Wang, Y., Santomasso, B., Mead, E., et al. (2018). Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. N Engl J Med 378, 449-459.2. Mardiana, S., Solomon, B.J., Darcy, P.K., and Beavis, P.A. (2019). Supercharging adoptive T cell therapy to overcome solid tumor–induced immunosuppression. Science Translational Medicine 11, eaaw2293.3. Tone M, Tone Y, Adams E, et al. Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells[J]. Proceedings of the National Academy of Sciences of the United States of America, 2003, 100(25): p.15059-15064.4. Stephens G L, Mchugh R S, Whitters M J, et al. Engagement of Glucocorticoid-Induced TNFR Family-Related Receptor on Effector T Cells by its Ligand Mediates Resistance to Suppression by CD4+CD25+ T Cells[J]. Journal of Immunology, 2004, 173(8):5008-5020.5.Shimizu J, Yamazaki S, Takahashi T, et al. Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance[J]. Nature Immunology, 2002, 3(2): 135-142.6.Rebecca, Mchugh, And, et al. CD4+CD25+ Immunoregulatory T Cells: Gene Expression Analysis Reveals a Functional Role for the Glucocorticoid-Induced TNF Receptor[J]. 2002, 6(5): 5-12.7. Binghe Tan#, Chuntian Tu#, Hao Xiong#, Yongqian Xu, Xiujuan Shi, Xiaolin Zhang, Ruijie Yang, Na Zhang, Boxu Lin, Mingyao Liu, Juliang Qin*, Bing Du*. (2023) LIGHT/TNFSF14 promotes CAR-T cell trafficking and cytotoxicity through reversing immunosuppressive tumor microenvironment. Molecular Therapy. 2025 Jan 25:S1525-0016(25)00040-1. doi: 10.1016/j.ymthe.2025.01.036. Online ahead of print.