Sim Hye-In, Jo Yunju, Ahn Hyejin, Hong Juyeon, Kim Hye-Bin, Yun Bohwan, Son Haeun, Jeong Yeonjun, Kim Jibaek, Park Chan-Sik, Park Yoon, Jin Hyung-Seung
Chemical and Biological Integrative Research Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792; Department of Life Sciences, Korea University, Seoul 02481, Korea.
Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
BMB Rep. 2025 Jul;58(7):307-312. doi: 10.5483/BMBRep.2025-0041.
Glioblastoma (GBM) frequently expresses cytomegalovirus (CMV) antigens, making CMV-specific CD8＋T cells attractive candidates for adoptive immunotherapy due to their longevity and inherent tumor reactivity. However, these T cells encounter significant immunosuppressive challenges within the GBM microenvironment, including cytokine scarcity and checkpointmediated inhibition, which limit their proliferation and function. Here, we assessed strategies to overcome these limitations by modulating immune checkpoint pathways. Antigen stimulation combined with IL-2 robustly expanded high-avidity (tetramer-high) CMV-specific T cells with significant enrichment of CD62L＋ central memory (TCM) cells. In contrast, antigen stimulation alone modestly expanded tetramer-high cells with limited TCM enrichment. PD-L1 blockade in the absence of IL-2 favored expansion of tetramer-high CMV-specific CD8＋T cells, preserved CD62L expression, and enhanced CD226 expression. Furthermore, combining anti-PD-L1 blockade with an anti-CD226 agonist markedly enhanced proliferation, IFN-γ production, and TCM enrichment in both tetramer-high and tetramer-low populations, reaching levels comparable to IL-2-supported conditions. Together, these findings highlight that simultaneous modulation of PD-L1 and CD226 pathways can restore CMV-specific T cell function, offering a promising strategy to boost TCR-T efficacy in cytokine-deprived environments. [BMB Reports 2025; 58(7): 307-312].
胶质母细胞瘤（GBM）经常表达巨细胞病毒（CMV）抗原，由于其寿命长和固有的肿瘤反应性，使得CMV特异性CD8＋T细胞成为过继性免疫治疗的有吸引力的候选者。然而，这些T细胞在GBM微环境中面临重大的免疫抑制挑战，包括细胞因子缺乏和检查点介导的抑制，这限制了它们的增殖和功能。在这里，我们评估了通过调节免疫检查点途径来克服这些限制的策略。抗原刺激与IL-2联合使用可强力扩增高亲和力（四聚体高）CMV特异性T细胞，并显著富集CD62L＋中央记忆（TCM）细胞。相比之下，单独的抗原刺激仅适度扩增四聚体高细胞，且TCM富集有限。在没有IL-2的情况下进行PD-L1阻断有利于四聚体高CMV特异性CD8＋T细胞的扩增，保留CD62L表达，并增强CD226表达。此外，将抗PD-L1阻断与抗CD226激动剂联合使用可显著增强四聚体高和四聚体低群体中的增殖、IFN-γ产生和TCM富集，达到与IL-2支持条件相当的水平。总之，这些发现突出表明，同时调节PD-L1和CD226途径可以恢复CMV特异性T细胞功能，为在细胞因子缺乏的环境中提高TCR-T疗效提供了一种有前景的策略。[《BMB报告》2025年；58(7): 307 - 312]
