Hye-In Sim Yunju Jo Hyejin Ahn Juyeon Hong Hye-bin Kim Bohwan Yun Haeun Son Yeonjun Jeong Jibaek Kim Chan-Sik Park Yoon Park Hyung-seung Jin 2025-08-04T02:30:09Z 2025-08-04T02:30:09Z 2025-08-01 2025-07 1976-6696 https://pubs.kist.re.kr/handle/201004/152928 Glioblastoma (GBM) frequently expresses cytomegalovirus (CMV)antigens, making CMV-specific CD8＋T cells attractive candidatesfor adoptive immunotherapy due to their longevity andinherent tumor reactivity. However, these T cells encountersignificant immunosuppressive challenges within the GBMmicroenvironment, including cytokine scarcity and checkpointmediatedinhibition, which limit their proliferation and function. Here, we assessed strategies to overcome these limitationsby modulating immune checkpoint pathways. Antigenstimulation combined with IL-2 robustly expanded high-avidity(tetramer-high) CMV-specific T cells with significant enrichmentof CD62L＋ central memory (TCM) cells. In contrast, antigenstimulation alone modestly expanded tetramer-high cells withlimited TCM enrichment. PD-L1 blockade in the absence of IL-2favored expansion of tetramer-high CMV-specific CD8＋T cells,preserved CD62L expression, and enhanced CD226 expression. Furthermore, combining anti-PD-L1 blockade with ananti-CD226 agonist markedly enhanced proliferation, IFN-？production, and TCM enrichment in both tetramer-high andtetramer-low populations, reaching levels comparable to IL-2-supported conditions. Together, these findings highlight thatsimultaneous modulation of PD-L1 and CD226 pathways canrestore CMV-specific T cell function, offering a promising strategyto boost TCR-T efficacy in cytokine-deprived environments. English 생화학분자생물학회 Modulating CD226 and PD-(L)1 pathways improves CMV-specific CD8＋T cell responses in the absence of IL-2 Article 10.5483/BMBRep.2025-0041 1 BMB Reports, v.58, no.7, pp.307 - 312 BMB Reports 58 7 307 312 Y scie scopus kci ART003228635 001578015800005 Biochemistry & Molecular Biology Biochemistry & Molecular Biology Article Cytotoxic T-Lymphocytes/immunology Immune Checkpoint Inhibitors/therapeutic use Programmed Cell Death 1 Receptor/antagonists & inhibitors CD226 Antigen/immunology Central Memory T-Cells/ immunology