<bold>Fibroblast Activation Protein-α</bold><bold> Expression in Cancer-Associated Fibroblasts Shows the Poor Survival of Colorectal Cancer via Immune-Mediated Pathways</bold>

BackgroundCancer-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-alpha (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.MethodsWe 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.ResultsAccording 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.ConclusionsThis 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.