Identification of cold tumor induction–related markers in pancreatic cancer and the clinical implication of PCDH7

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is considered a “cold” tumor because the tumor immune microenviron- ment (TIME) exhibits poor intratumoral T-cell infiltration. This study aimed to identify the marker genes associated with induction of cold TIME in PDAC cells. Methods: We orthotopically transplanted 10 primary cultures of PDAC derived from KrasG12D/+; Trp53R172H/+; Pdx-1- Cre (KPC) mice into immunocompetent mice and evaluated TIME by immunohistochemistry (IHC) staining of CD8. We divided primary cultures into two groups: cold TIME group with low CD8+ T-cell infiltration and a hot TIME group with high infiltration. RNA sequencing was performed to identify specific genes in the cold TIME group, and single-cell RNA sequencing (scRNA-seq) data was used for validation. IHC was performed to evaluate expressions in human PDAC samples. Results: We identified six genes specific in PDAC cells to the cold TIME group by RNA sequencing; these were defined as “cold tumor induction–related genes”. Human PDAC scRNA-seq data revealed that cold tumor induction–related genes were significantly and negatively correlated with the number of CD8+ T-cells (p = 0.0341). These genes included protocad- herin 7 (PCDH7). High expression of PCDH7 significantly and negatively correlated with the number of CD8+ T-cells in scRNA-seq (p = 0.0474) and IHC (p = 0.0110) data using human PDAC samples. PCDH7 was an independent factor for poor prognosis in PDAC (overall survival: hazard ratio = 2.07, p = 0.0367). Conclusion: PCDH7 is a prognostic marker associated with CD8+ T-cell infiltration for PDAC patients.