Deregulated Mucosal Immune Surveillance through Gut-Associated Regulatory T Cells and PD-1 + T Cells in Human Colorectal Cancer

• Published in: The Journal of immunology (1950) 2018-05, Vol.200 (9), p.3291-3303
• Main Authors: Fujimoto, Hanae, Saito, Yoriko, Ohuchida, Kenoki, Kawakami, Eiryo, Fujiki, Saera, Watanabe, Takashi, Ono, Rintaro, Kaneko, Akiko, Takagi, Shinsuke, Najima, Yuho, Hijikata, Atsushi, Cui, Lin, Ueki, Takashi, Oda, Yoshinao, Hori, Shohei, Ohara, Osamu, Nakamura, Masafumi, Saito, Takashi, Ishikawa, Fumihiko
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adenocarcinoma - immunology; Aged; Anergy; Apoptosis; Carbon tetrachloride; Carcinogenesis; CCR1 protein; CCR8 protein; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - immunology; Cytotoxicity; Drug development; Epithelial cells; Epithelium; Female; Foxp3 protein; Gene expression; Humans; Immunity, Mucosal - immunology; Immunologic Surveillance - immunology; Immunological tolerance; Immunoregulation; Immunosurveillance; Intestinal Mucosa - immunology; Intestine; Lymphocytes; Lymphocytes T; Male; Metastases; Middle Aged; Mucosal immunity; PD-1 protein; Programmed Cell Death 1 Receptor; Stromal cells; T-Lymphocytes, Regulatory - immunology; Tumor Escape - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1701222

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 , , and , whereas their ligands and were found upregulated in cancerous epithelium. Overexpression of and , 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.