Chang Jiang, Feng Qingyang, Mao Yihao, Zhang Zhiyuan, Xu Yuqiu, Chen Yijiao, Zheng Peng, Lin Songbin, Shen Feifan, Zhang Zhuojian, Zhang Ziqi, He Guodong, Xu Jianmin, Wei Ye
Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Huadong Hospital, Fudan University, Shanghai, China.
Colorectal Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, China.
Int Immunopharmacol. 2024 Mar 30;130:111771. doi: 10.1016/j.intimp.2024.111771. Epub 2024 Mar 2.
Siglec9 has been identified as an immune checkpoint molecule on tumor-associated macrophages (TAMs). Nevertheless, the expression profile and clinical significance of Siglec9 + TAMs in colon cancer (CC) are still not fully understood.
Two clinical cohorts from distinct medical centers were retrospectively enrolled. Immunohistochemistry and immunofluorescence were conducted to evaluate the infiltration of immune cells. Single-cell RNA sequencing and flow cytometry were utilized to identify the impact of Siglec9 + TAMs on the tumor immune environment, which was subsequently validated through bioinformatics analysis of the TCGA database. Prognosis and the benefit of adjuvant chemotherapy (ACT) were also evaluated using Cox regression analysis and the Kaplan-Meier method.
High infiltration of Siglec9 + TAMs was associated with worse prognosis and better benefit from 6-month ACT. Siglec9 + TAMs contributed to immunoevasion by promoting the infiltration of immunosuppressive cells and the dysfunction process of CD8 + T cells. Additionally, high infiltration of Siglec9 + TAMs was associated with the mesenchymal-featured subtype and overexpression of the VEGF signaling pathway, which was validated by the strongest communication between Siglec9 + TAMs and vascular endothelial cells.
Siglec9 + TAMs may serve as a biomarker for prognosis and response to ACT in CC. Furthermore, the immunoevasive contexture and angiogenesis stimulated by Siglec9 + TAMs suggest potential treatment combinations for CC patients.
Siglec9已被确定为肿瘤相关巨噬细胞（TAM）上的一种免疫检查点分子。然而，Siglec9 + TAM在结肠癌（CC）中的表达谱及临床意义仍未完全明确。
回顾性纳入来自不同医疗中心的两个临床队列。采用免疫组织化学和免疫荧光法评估免疫细胞浸润情况。利用单细胞RNA测序和流式细胞术确定Siglec9 + TAM对肿瘤免疫环境的影响，随后通过对TCGA数据库的生物信息学分析进行验证。还使用Cox回归分析和Kaplan-Meier方法评估预后及辅助化疗（ACT）的获益情况。
Siglec9 + TAM的高浸润与较差的预后相关，且从6个月的ACT中获益更多。Siglec9 + TAM通过促进免疫抑制细胞浸润和CD8 + T细胞功能障碍过程导致免疫逃逸。此外，Siglec9 + TAM的高浸润与间充质特征亚型及VEGF信号通路的过表达相关，这通过Siglec9 + TAM与血管内皮细胞之间最强的通讯得到验证。
Siglec9 + TAM可能作为CC患者预后及对ACT反应的生物标志物。此外，Siglec9 + TAM刺激的免疫逃逸结构和血管生成提示了CC患者潜在的联合治疗方案。
