PD-L1 upregulation is associated with activation of the DNA double-strand break repair pathway in patients with colitic cancer

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 transcriptionall...

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Veröffentlicht in:Scientific reports 2021-06, Vol.11 (1), p.13077-10, Article 13077
Hauptverfasser: Ozawa, Naoya, Yokobori, Takehiko, Osone, Katsuya, Katayama, Chika, Suga, Kunihiko, Komine, Chika, Shibasaki, Yuta, Shiraishi, Takuya, Okada, Takuhisa, Kato, Ryuji, Ogawa, Hiroomi, Sano, Akihiko, Sakai, Makoto, Sohda, Makoto, Ojima, Hitoshi, Miyazaki, Tatsuya, Motegi, Yoko, Ide, Munenori, Yao, Takashi, Kuwano, Hiroyuki, Shirabe, Ken, Saeki, Hiroshi
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Sprache:eng
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Zusammenfassung: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-021-92530-3