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

• DOI: 10.1007/s00432-025-06095-z
• Publication Date: 2025-01-24T17:52:52Z
• Authors: Yuki Mochida; Kenoki Ohuchida; Bo Zhang; Yutaka Yamada; Chikanori Tsutsumi; Akihiro Kubo; Koki Oyama; Tomohiko Shinkawa; Chika Iwamoto; Nobuhiro Torata; Toshiya Abe; Noboru Ideno; Naoki Ikenaga; Kohei Nakata; Yoshinao Oda; Masafumi Nakamura
• Keywords: Tumor microenvironment; Research; Tumor escape; CD8-positive T-lymphocytes; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Pancreatic cancer; PCDH7 protein; RC254-282

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is considered a “cold” tumor because the tumor immune microenvironment (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 protocadherin 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00432-025-06095-z.