Zhuang Meng, Liu Jialiang, Li Yuegang, Zhang Jinzhu, Jiang Zheng, Wang Xishan, Tang Jianqiang
Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Oncogene. 2025 Feb;44(6):378-390. doi: 10.1038/s41388-024-03223-w. Epub 2024 Nov 18.
Tumor-infiltrating lymphocytes can influence tumorigenesis and progression. We found PD-L1 can inhibit the infiltration of memory T (Tm) cells in vivo and in vitro by reducing the secretion of CXCL9, CXCL10 in colorectal cancer. Patients with high PD-L1 expression have minimal Tm cell infiltration, accompanied with a higher incidence of tumor metastasis. Single-cell sequencing revealed that PD-L1 mainly inhibited the infiltration of a specific Tm cell subset characterized by the expression of FGFBP2 gene. To clarify the distribution of FGFBP2(+)Tm cells, peripheral blood, lymph nodes, colon polyps, primary tumor, and liver metastases samples were collected. As the tumor progressed, the infiltration of FGFBP2(+) memory T cells gradually increased and accumulated in liver metastases. By establishing a mouse metastasis model, we found in high PD-L1 expression group, the luciferin intensity of metastatic tumor was significantly higher, the number of metastatic nodules and the weight of metastases were also increased. The number of FGFBP2(+) Tm cells in peripheral blood and in liver/lung metastases were increased. Therefore, the expression of PD-L1 in primary tumor can promote the occurrence of metastases, and FGFBP2(+)Tm cells may be involved in the formation of metastases. Furthermore, the result showed that the number of FGFBP2(+) Tm cells in metastases was positively correlated with the number of vessels in liver/lung metastases. In conclusion, we confirmed that the expression of PD-L1 in primary tumor can increase the number of FGFBP2(+) Tm cells in peripheral blood and promote tumor metastasis, which is likely to be caused by the angiogenesis of FGFBP2(+) Tm cells in metastases.
肿瘤浸润淋巴细胞可影响肿瘤的发生和进展。我们发现，在结直肠癌中，程序性死亡配体1（PD-L1）可通过减少CXC趋化因子配体9（CXCL9）、CXC趋化因子配体10（CXCL10）的分泌，在体内和体外抑制记忆T（Tm）细胞的浸润。PD-L1高表达的患者Tm细胞浸润极少，且肿瘤转移发生率较高。单细胞测序显示，PD-L1主要抑制以成纤维细胞生长因子结合蛋白2（FGFBP2）基因表达为特征的特定Tm细胞亚群的浸润。为明确FGFBP2（+）Tm细胞的分布，我们收集了外周血、淋巴结、结肠息肉、原发性肿瘤及肝转移灶样本。随着肿瘤进展，FGFBP2（+）记忆T细胞浸润逐渐增加并在肝转移灶中积聚。通过建立小鼠转移模型，我们发现，在PD-L1高表达组中，转移瘤的荧光素强度显著更高，转移结节数量及转移灶重量也增加。外周血以及肝/肺转移灶中FGFBP2（+）Tm细胞数量增加。因此，原发性肿瘤中PD-L1的表达可促进转移的发生，且FGFBP2（+）Tm细胞可能参与转移灶的形成。此外，结果显示，转移灶中FGFBP2（+）Tm细胞数量与肝/肺转移灶中的血管数量呈正相关。总之，我们证实原发性肿瘤中PD-L1的表达可增加外周血中FGFBP2（+）Tm细胞数量并促进肿瘤转移，这可能是由转移灶中FGFBP2（+）Tm细胞的血管生成所致。
