Department of Oncology, Zoucheng People's Hospital, Jining City, China.
Department of Oncology, Shandong Chengwu County People's Hospital, Heze City, China.
J Gastroenterol Hepatol. 2022 Jan;37(1):154-163. doi: 10.1111/jgh.15730. Epub 2021 Nov 12.
CD155/T-cell immunoglobulin and ITIM domain (TIGIT) suppressed anti-cancer immunity in several cancers, but its roles in colorectal cancer (CRC) were not clear. Here, we investigated its roles in CRC.
The percentages of CD8 T cells expressing TIGIT and secreting cytokines (IL-2, TNF-α, and IFNγ) were evaluated by flow cytometry. The expression level of CD155 was determined by western blot and immunohistochemistry. The levels of cytokines were determined by enzyme-linked immunosorbent assay. The activation of the nuclear factor-kappa B (NF-κB) pathway was examined by western blot and immunofluorescent assay.
T-cell immunoglobulin and ITIM domain was overexpressed on CD8 T cells of CRC patients and mice. CD155 was overexpressed in mice CRC tissues and cells. The addition of CD155 recombinant protein could decrease the percentages of CD8 T cells secreting cytokines. Blocking TIGIT could increase the percentages of cytokine-secreting CD8 T cells. Coculturing with CD155-knockdown CRC cells could upregulate the percentages of CD8 T cells secreting cytokines. Blocking TIGIT partially counteracted the effect of the knockdown of CD155. Besides, coculturing with CD155-knockdown CRC cells could promote the secretion of cytokines, activate the NF-κB pathway, and enhance the nuclear translocation of p65. And these effects were counteracted by the application of an NF-κB inhibitor. Finally, blocking TIGIT played anti-cancer roles such as suppression of tumor growth, increasing the percentages of cytokine-secreting CD8 T cells and activation of the NF-κB signaling pathway.
Suppressing CD155/TIGIT exerted anti-cancer effects against CRC, and our findings provided a potential therapeutic approach to treat CRC.
CD155/T 细胞免疫球蛋白和 ITIM 结构域（TIGIT）在几种癌症中抑制抗肿瘤免疫，但在结直肠癌（CRC）中的作用尚不清楚。在这里，我们研究了它在 CRC 中的作用。
通过流式细胞术评估表达 TIGIT 和分泌细胞因子（IL-2、TNF-α 和 IFNγ）的 CD8 T 细胞的百分比。通过 Western blot 和免疫组织化学测定 CD155 的表达水平。通过酶联免疫吸附试验测定细胞因子的水平。通过 Western blot 和免疫荧光测定测定核因子-κB（NF-κB）途径的激活。
CRC 患者和小鼠的 CD8 T 细胞上 T 细胞免疫球蛋白和 ITIM 结构域过度表达。CD155 在小鼠 CRC 组织和细胞中过度表达。添加 CD155 重组蛋白可降低分泌细胞因子的 CD8 T 细胞的百分比。阻断 TIGIT 可增加分泌细胞因子的 CD8 T 细胞的百分比。与 CD155 敲低 CRC 细胞共培养可上调分泌细胞因子的 CD8 T 细胞的百分比。阻断 TIGIT 部分抵消了 CD155 敲低的作用。此外，与 CD155 敲低 CRC 细胞共培养可促进细胞因子的分泌，激活 NF-κB 途径，并增强 p65 的核转位。NF-κB 抑制剂的应用可抵消这些作用。最后，阻断 TIGIT 发挥抗癌作用，如抑制肿瘤生长、增加分泌细胞因子的 CD8 T 细胞的百分比和激活 NF-κB 信号通路。
抑制 CD155/TIGIT 对 CRC 具有抗癌作用，我们的研究结果为治疗 CRC 提供了一种潜在的治疗方法。
