Qin Yubo, Miyake Toru, Muramoto Keiji, Maekawa Takeru, Nishina Yusuke, Wang Ying, Shimizu Tomoharu, Tani Masaji
Department of Surgery, Shiga University of Medical Science, Shiga, Japan.
Department of Emergency Center, Inner Mongolia Autonomous Region People's Hospital, Hohhot, China.
Ann Surg Oncol. 2025 Mar;32(3):1941-1952. doi: 10.1245/s10434-024-16593-y. Epub 2024 Dec 2.
Cancer-associated fibroblasts (CAFs) and immune cells, the key components of the tumor microenvironment (TME), play critical roles in oncogenesis. Despite the recognized function of fibroblast activation protein-α (FAP), a specific biomarker of CAFs in cancer progression, its role in the survival of patients with colorectal cancer (CRC) and tumor immune microenvironment (TIME) remains unclear.
We investigated 180 pathological sections obtained from 178 consecutive patients with CRC who underwent surgical resection at Shiga University of Medical Science Hospital between January 2013 and December 2015. FAP expression levels and CD3 and CD8 densities at the invasive margin and center of tumor were assessed using immunohistochemical (IHC) staining. Furthermore, we used single-cell RNA sequencing (scRNA-seq) of CAFs in a separate cohort of 10 untreated patients with CRC derived from the Gene Expression Omnibus database.
According to IHC evaluation, high FAP expression in patients with CRC showed a correlation with reduced tumor-infiltrating lymphocyte (TIL) distribution and poor survival. Based on the FAP transcription levels obtained through scRNA-seq analysis, CAFs were grouped into high and low FAP expression groups. Elevated FAP expression was correlated with decreased expression of T- and B-cell biomarkers, suggesting an association with an immunosuppressive TME promotion. Several genes associated with cancer-related immune-mediated pathways (CXCL12, COL11A1, CCL11, and COL10A1) were significantly upregulated in FAP-positive CAFs.
This study highlights the effects of FAP expression on survival of patients with CRC, its interaction with TILs, and relevant signaling pathways, and underscores potential immunotherapeutic targets for future investigation.
癌症相关成纤维细胞（CAFs）和免疫细胞是肿瘤微环境（TME）的关键组成部分，在肿瘤发生过程中发挥着关键作用。尽管成纤维细胞活化蛋白-α（FAP）作为CAFs在癌症进展中的一种特异性生物标志物，其功能已得到认可，但其在结直肠癌（CRC）患者生存及肿瘤免疫微环境（TIME）中的作用仍不明确。
我们研究了2013年1月至2015年12月期间在滋贺医科大学医院接受手术切除的178例连续CRC患者的180份病理切片。采用免疫组织化学（IHC）染色评估肿瘤浸润边缘和中心的FAP表达水平以及CD3和CD8密度。此外，我们对来自基因表达综合数据库的另外10例未经治疗的CRC患者队列中的CAFs进行了单细胞RNA测序（scRNA-seq）。
根据IHC评估，CRC患者中FAP高表达与肿瘤浸润淋巴细胞（TIL）分布减少及生存不良相关。基于通过scRNA-seq分析获得的FAP转录水平，将CAFs分为FAP高表达组和低表达组。FAP表达升高与T细胞和B细胞生物标志物表达降低相关，提示与免疫抑制性TME促进有关。在FAP阳性的CAFs中，几个与癌症相关免疫介导途径相关的基因（CXCL12、COL11A1、CCL11和COL10A1）显著上调。
本研究突出了FAP表达对CRC患者生存的影响、其与TILs的相互作用以及相关信号通路，并强调了未来研究潜在的免疫治疗靶点。
