Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia.
Federation University, Ballarat, VIC 3350, Australia.
Cells. 2024 Oct 26;13(21):1777. doi: 10.3390/cells13211777.
Inhibitory receptors are critical for regulating immune cell function. In cancer, these receptors are often over-expressed on the cell surface of T and NK cells, leading to reduced anti-tumor activity. Here, through the analysis of 11 commonly studied checkpoint and inhibitory receptors, we discern that only (TIM3) and (CD39) display significantly greater gene expression in glioblastoma compared to normal brain and lower grade glioma. Cell surface TIM-3, but not ENTPD1, was also elevated on activated CD4 and CD8 T cells, as well as on NK cells from glioblastoma patients compared to healthy donor T and NK cells. A subsequent analysis of molecules known to co-ordinate TIM-3 function and regulation was performed, which revealed that BAT3 expression was significantly reduced in CD4 and CD8 T cells, as well as NK cells from glioblastoma patients compared to counterparts from healthy donors. These pro-inhibitory changes are also correlated with reduced levels of the activation marker CD69 and the pro-inflammatory cytokine IFNγ in CD4 and CD8 T cells, as well as NK cells from glioblastoma patients. Collectively, these data reveal that glioblastoma-mediated CD4 and CD8 T cell and NK cell suppression is due, at least in part, to dysregulated TIM-3 and BAT3 expression and the associated downstream immunoregulatory and dysfunctional effects.
抑制性受体对于调节免疫细胞功能至关重要。在癌症中，这些受体通常在 T 和 NK 细胞的细胞表面过度表达，导致抗肿瘤活性降低。在这里，通过对 11 种常见的检查点和抑制性受体进行分析，我们发现只有 (TIM3) 和 (CD39) 在胶质母细胞瘤中与正常大脑和低级别胶质瘤相比，基因表达显著更高。细胞表面 TIM-3，但不是 ENTPD1，也在激活的 CD4 和 CD8 T 细胞以及来自胶质母细胞瘤患者的 NK 细胞上升高，而与来自健康供体的 T 和 NK 细胞相比。随后对已知协调 TIM-3 功能和调节的分子进行了分析，结果表明，与来自健康供体的对应物相比，CD4 和 CD8 T 细胞以及来自胶质母细胞瘤患者的 NK 细胞中 BAT3 的表达显著降低。这些促抑制性变化与 CD4 和 CD8 T 细胞以及来自胶质母细胞瘤患者的 NK 细胞中激活标志物 CD69 和促炎细胞因子 IFNγ 的水平降低相关。总之，这些数据表明，胶质母细胞瘤介导的 CD4 和 CD8 T 细胞和 NK 细胞抑制至少部分归因于 TIM-3 和 BAT3 表达的失调以及相关的下游免疫调节和功能障碍效应。
