Teruya Yasuhiko, Yamaguchi Kosuke, Yamane Kohei, Miyake Naomi, Nakayama Yuji, Nonaka Takafumi, Chikumi Hiroki, Yamasaki Akira
Division of Respiratory Medicine and Rheumatology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan.
Division of Radioisotope Science, Research Initiative Center, Organization for Research Initiative and Promotion, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan.
Cells. 2025 Jun 13;14(12):893. doi: 10.3390/cells14120893.
UL16-binding protein 2 (ULBP2), a ligand for the activating receptor NKG2D, plays a dual role in tumor immunity, promoting immune activation or suppression, depending on the context. To investigate its impact on CD4CD25 T cell-targeted immunotherapies, we used a syngeneic CT26 colon cancer model engineered to express ULBP2 and compared tumor growth and tumor-infiltrating lymphocyte (TIL) profiles in control and ULBP2-expressing tumors treated with anti-CD4, anti-CD25, or anti-CTLA-4 antibodies. Tumor growth was uniformly assessed on day 21 post-transplantation, and TIL analysis was performed in groups with evaluable residual tumors. Anti-CD4 antibody significantly suppressed tumor growth in mock-transfected tumors, while no significant suppression was observed in ULBP2-expressing tumors. Anti-CD25 antibody had limited efficacy in mock tumors and tended to promote tumor growth in ULBP2-expressing tumors. Following these treatments, ULBP2 expression was associated with reduced NKG2D expression in CD8 effector memory T cells, particularly PD-1 subsets. In contrast, anti-CTLA-4 antibody treatment induced marked tumor regression irrespective of ULBP2 expression. These findings suggest that ULBP2-NKG2D signaling may contribute to altered CD8 T cell phenotypes under T cell-modulatory conditions, potentially impacting the outcome of CD4CD25 T cell-targeted therapies and providing insights for optimizing immunotherapeutic strategies.
UL16结合蛋白2（ULBP2）是激活受体NKG2D的配体，在肿瘤免疫中发挥双重作用，根据具体情况促进免疫激活或抑制。为了研究其对靶向CD4CD25 T细胞的免疫疗法的影响，我们使用了一种经基因工程改造以表达ULBP2的同基因CT26结肠癌模型，并比较了用抗CD4、抗CD25或抗CTLA-4抗体治疗的对照肿瘤和表达ULBP2的肿瘤中的肿瘤生长和肿瘤浸润淋巴细胞（TIL）谱。在移植后第21天统一评估肿瘤生长情况，并对有可评估残留肿瘤的组进行TIL分析。抗CD4抗体显著抑制了 mock 转染肿瘤的生长，而在表达ULBP2的肿瘤中未观察到显著抑制作用。抗CD25抗体在 mock 肿瘤中的疗效有限，并且在表达ULBP2的肿瘤中倾向于促进肿瘤生长。经过这些治疗后，ULBP2的表达与CD8效应记忆T细胞，特别是PD-1亚群中NKG2D表达的降低有关。相比之下，抗CTLA-4抗体治疗无论ULBP2表达如何均诱导明显的肿瘤消退。这些发现表明，ULBP2-NKG2D信号传导可能在T细胞调节条件下导致CD8 T细胞表型改变，可能影响靶向CD4CD25 T细胞疗法的结果，并为优化免疫治疗策略提供见解。
