Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China; Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
Department of Anorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
Int Immunopharmacol. 2023 Aug;121:110457. doi: 10.1016/j.intimp.2023.110457. Epub 2023 Jun 16.
T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) is a vital immune checkpoint that regulates the immune response. However, the specific role of TIM3 in patients with colorectal cancer (CRC) have rarely been studied. In this study, we investigated the effect of TIM3 on CD8 T cells in CRC and explored the mechanism of TIM3 regulation in tumor microenvironment (TME).
Peripheral blood and tumor tissues of patients with CRC were collected to evaluate TIM3 expression using flow cytometry. Cytokines in the serum of healthy donors and patients with early- and advanced-stage CRC were screened using a multiplex assay. The effects of interleukin-8 (IL8) on TIM3 expression on CD8 T cells were analyzed using cell incubation experiments in vitro. The correlation between TIM3 or IL8 and prognosis was verified using bioinformatics analysis.
TIM3 expression on CD8 T cells was obviously reduced in patients with advanced-stage CRC, whereas a lower TIM3 expression level was associated with poorer prognosis. Macrophage-derived IL8, which could inhibit TIM3 expression on CD8 T cells, was significantly increased in the serum of patients with advanced CRC. In addition, the function and proliferation of CD8 and TIM3CD8 T cells were inhibited by IL8, which was partly depending on TIM3 expression. The inhibitory effects of IL8 were reversed by anti-IL8 and anti-CXCR2 antibodies.
In summary, macrophages-derived IL8 suppresses TIM3 expression on CD8 T cells through CXCR2. Targeting the IL8/CXCR2 axis may be an effective strategy for treating patients with advanced CRC.
T 细胞免疫球蛋白和粘蛋白结构域蛋白 3（TIM3）是一种重要的免疫检查点，调节免疫反应。然而，TIM3 在结直肠癌（CRC）患者中的具体作用很少被研究。在这项研究中，我们研究了 TIM3 对 CRC 中 CD8 T 细胞的影响，并探讨了 TIM3 在肿瘤微环境（TME）中的调节机制。
收集 CRC 患者的外周血和肿瘤组织，通过流式细胞术评估 TIM3 的表达。使用多重分析筛选健康供体和早期及晚期 CRC 患者血清中的细胞因子。通过体外细胞孵育实验分析白细胞介素 8（IL8）对 CD8 T 细胞 TIM3 表达的影响。使用生物信息学分析验证 TIM3 或 IL8 与预后的相关性。
晚期 CRC 患者 CD8 T 细胞上 TIM3 的表达明显降低，而较低的 TIM3 表达水平与预后较差相关。晚期 CRC 患者血清中巨噬细胞衍生的 IL8 显著增加，可抑制 CD8 T 细胞上 TIM3 的表达。此外，IL8 抑制 CD8 和 TIM3+CD8 T 细胞的功能和增殖，部分依赖于 TIM3 的表达。IL8 的抑制作用可被抗 IL8 和抗 CXCR2 抗体逆转。
总之，巨噬细胞衍生的 IL8 通过 CXCR2 抑制 CD8 T 细胞上 TIM3 的表达。靶向 IL8/CXCR2 轴可能是治疗晚期 CRC 患者的有效策略。
