Deregulated mucosal immune surveillance through gut-Associated regulatory t cells and PD-1 + t cells in human colorectal cancer

Hanae Fujimoto, Yoriko Saito, Kenoki Ohuchida, Eiryo Kawakami, Saera Fujiki, Takashi Watanabe, Rintaro Ono, Akiko Kaneko, Shinsuke Takagi, Yuho Najima, Atsushi Hijikata, Lin Cui, Takashi Ueki, Yoshinao Oda, Shohei Hori, Osamu Ohara, Masafumi Nakamura, Takashi Saito, Fumihiko Ishikawa

研究成果: Contribution to journalArticle査読

12 被引用数 (Scopus)

抄録

Disturbed balance between immune surveillance and tolerance May lead to poor clinical outcomes in some malignancies. In paired analyses of adenocarcinoma and normal mucosa from 142 patients, we found a significant increase of the CD4/CD8 ratio and accumulation of regulatory T cells (Tregs) within the adenocarcinoma. The increased frequency of Tregs correlated with the local infiltration and extension of the tumor. There was concurrent maturation arrest, upregulation of programmed death-1 expression, and functional impairment in CD8 + T cells (CTLs) isolated from the adenocarcinoma. Adenocarcinoma-associated Tregs directly inhibit the function of normal human CTLs in vitro. With histopathological analysis, Foxp3 + Tregs were preferentially located in stroma. Concurrent transcriptome analysis of epithelial cells, stromal cells, and T cell subsets obtained from carcinomatous and normal intestinal samples from patients revealed a distinct gene expression signature in colorectal adenocarcinoma–associated Tregs, with overexpression of CCR1, CCR8, and TNFRSF9, whereas their ligands CCL4 and TNFSF9 were found upregulated in cancerous epithelium. Overexpression of WNT2 and CADM1, associated with carcinogenesis and metastasis, in cancer-associated stromal cells suggests that both cancer cells and stromal cells play important roles in the development and progression of colorectal cancer through the formation of a tumor microenvironment. The identification of CTL anergy by Tregs and the unique gene expression signature of human Tregs and stromal cells in colorectal cancer patients May facilitate the development of new therapeutics against malignancies. The Journal of Immunology, 2018, 200: 3291–3303.

本文言語英語
ページ(範囲)3291-3303
ページ数13
ジャーナルJournal of Immunology
200
9
DOI
出版ステータス出版済み - 5 1 2018

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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