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Abstract
Ulcerative colitis (UC) is a DNA damage-associated chronic inflammatory disease; the DNA double-strand break (DSB) repair pathway participates in UC-associated dysplasia/colitic cancer carcinogenesis. The DSB/interferon regulatory factor-1 (IRF-1) pathway can induce PD-L1 expression transcriptionally. However, the association of PD-L1/DSB/IRF-1 with sporadic colorectal cancer (SCRC), and UC-associated dysplasia/colitic cancer, remains elusive. Therefore, we investigated the significance of the PD-L1/DSB repair pathway using samples from 17 SCRC and 12 UC patients with rare UC-associated dysplasia/colitic cancer cases by immunohistochemical analysis. We compared PD-L1 expression between patients with SCRC and UC-associated dysplasia/colitic cancer and determined the association between PD-L1 and the CD8+ T-cell/DSB/IRF-1 axis in UC-associated dysplasia/colitic cancer. PD-L1 expression in UC and UC-associated dysplasia/colitic cancer was higher than in normal mucosa or SCRC, and in CD8-positive T lymphocytes in UC-associated dysplasia/colitic cancer than in SCRC. Moreover, PD-L1 upregulation was associated with γH2AX (DSB marker) and IRF-1 upregulation in UC-associated dysplasia/colitic cancer. IRF-1 upregulation was associated with γH2AX upregulation in UC-associated dysplasia/colitic cancer but not in SCRC. Multicolour immunofluorescence staining validated γH2AX/IRF-1/PD-L1 co-expression in colitic cancer tissue sections. Thus, immune cell-induced inflammation might activate the DSB/IRF-1 axis, potentially serving as the primary regulatory mechanism of PD-L1 expression in UC-associated carcinogenesis.
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Details
1 Gunma University, Department of General Surgical Science, Graduate School of Medicine, Maebashi, Japan (GRID:grid.256642.1) (ISNI:0000 0000 9269 4097)
2 Gunma University Initiative for Advanced Research (GIAR), Division of Integrated Oncology Research, Maebashi, Japan (GRID:grid.256642.1) (ISNI:0000 0000 9269 4097)
3 Gunma Prefectural Cancer Center, Department of Gastroenterological Surgery, Ohta, Japan (GRID:grid.256642.1)
4 Maebashi Red Cross Hospital, Department of Gastroenterological Surgery, Maebashi, Japan (GRID:grid.416269.e) (ISNI:0000 0004 1774 6300)
5 Maebashi Red Cross Hospital, Department of Pathology Diagnosis, Maebashi, Japan (GRID:grid.416269.e) (ISNI:0000 0004 1774 6300)
6 Juntendo University, Department of Human Pathology, Graduate School of Medicine, Bunkyo City, Tokyo, Japan (GRID:grid.258269.2) (ISNI:0000 0004 1762 2738)