Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
Anticancer Res. 2024 Sep;44(9):3757-3769. doi: 10.21873/anticanres.17200.
BACKGROUND/AIM: Recent studies suggest that PD-L1 expression in immune cells, rather than tumor cells, plays a key role in tumor immunity. Trefoil factor family 1 (TFF1) is a secreted protein expressed mainly by the gastrointestinal epithelium and is related to the development of malignant disease. This study investigated the effects of TFF1 on tumor immunity in a xenograft mouse model of colorectal cancer (CRC).
MC38 cells were implanted in wild-type (WT) and TFF1KO mice, and the tumor micro-environment was investigated using immunohistochemistry. The circulating immune cells were analyzed using flow cytometry.
Tumor growth was suppressed in TFF1KO mice. In the tumor microenvironment, CD8- and CD4-positive T cells and CD11c-positive dendritic cells (DCs) were frequently found in TFF1KO mice. When an immune checkpoint inhibitor was administered to these mice, almost half of the tumors in TFF1KO mice showed a complete response. The number of circulating PD-L1/DCs was markedly associated with tumor volume, with TFF1 deletion accelerating this effect and its injection decreasing it. These findings indicate that loss of TFF1 activates tumor immunity via frequent T-cell priming by DCs, and eventually suppresses tumor growth in CRC. In addition, the number of circulating PD-L1/DCs was identified as a predictive marker of checkpoint-inhibiting therapy efficacy.
Loss of TFF1 resulted in accelerated immune response to colorectal cancer. Further studies are needed to investigate the precise mechanisms of TFF1 in immunotolerance and develop a novel TFF1-inhibiting immunotherapeutic strategy for CRC.
背景/目的：最近的研究表明，免疫细胞而非肿瘤细胞中的 PD-L1 表达在肿瘤免疫中发挥关键作用。三叶因子家族 1（TFF1）是一种主要由胃肠道上皮细胞表达的分泌蛋白，与恶性疾病的发展有关。本研究在结直肠癌（CRC）的异种移植小鼠模型中研究了 TFF1 对肿瘤免疫的影响。
将 MC38 细胞植入野生型（WT）和 TFF1KO 小鼠中，并使用免疫组织化学法研究肿瘤微环境。使用流式细胞术分析循环免疫细胞。
TFF1KO 小鼠中的肿瘤生长受到抑制。在肿瘤微环境中，TFF1KO 小鼠中经常发现 CD8 和 CD4 阳性 T 细胞和 CD11c 阳性树突状细胞（DC）。当给这些小鼠施用免疫检查点抑制剂时，TFF1KO 小鼠的近一半肿瘤显示完全缓解。循环 PD-L1/DC 数量与肿瘤体积明显相关，TFF1 缺失加速了这种效应，而其注射则降低了这种效应。这些发现表明，TFF1 的缺失通过 DC 频繁地引发 T 细胞启动来激活肿瘤免疫，并最终抑制 CRC 中的肿瘤生长。此外，循环 PD-L1/DC 的数量被确定为检查点抑制治疗疗效的预测标志物。
TFF1 的缺失导致对结直肠癌的免疫反应加速。需要进一步研究 TFF1 在免疫耐受中的精确机制，并开发针对 CRC 的新型 TFF1 抑制免疫治疗策略。
