Distinct roles for interleukin-23 receptor signaling in regulatory T cells in sporadic and inflammation-associated carcinogenesis.

Autor:	Jacobse J; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States.; Department of Pediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, Netherlands.; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States.; Department of Medicine, Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, United States., Pilat JM; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States.; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United States., Li J; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States., Brown RE; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United States.; Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, TN, United States., Kwag A; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States., Buendia MA; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Monroe Carell Jr. Children's Hospital at Vanderbilt, Vanderbilt University Medical Center, Nashville, TN, United States., Choksi YA; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States.; Department of Medicine, Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, United States.; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United States.; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, United States., Washington MK; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States., Williams CS; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States.; Department of Medicine, Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, United States.; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United States.; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, United States., Markham NO; Department of Medicine, Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, United States., Short SP; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States.; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United States.; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, United States., Goettel JA; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States.; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States.; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United States.; Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, United States.; Vanderbilt Institute for Infection, Immunology and Inflammation, Vanderbilt University Medical Center, Nashville, TN, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in oncology [Front Oncol] 2024 Feb 05; Vol. 13, pp. 1276743. Date of Electronic Publication: 2024 Feb 05 (Print Publication: 2023).
DOI:	10.3389/fonc.2023.1276743
Abstrakt:	Introduction: The pro-inflammatory cytokine interleukin-23 (IL-23) has been implicated in colorectal cancer (CRC). Yet, the cell-specific contributions of IL-23 receptor (IL-23R) signaling in CRC remain unknown. One of the cell types that highly expresses IL-23R are colonic regulatory T cells (Treg cells). The aim of this study was to define the contribution of Treg cell-specific IL-23R signaling in sporadic and inflammation-associated CRC. Methods: In mice, the role of IL-23R in Treg cells in colitis-associated cancer (CAC) was investigated using azoxymethane/dextran sodium sulphate in wild-type Treg cell reporter mice (WT, Foxp3 YFP-iCre ), and mice harboring a Treg cell-specific deletion of IL-23 ( Il23r ΔTreg ). The role of IL-23R signaling in Treg cells in sporadic CRC was examined utilizing orthotopic injection of the syngeneic colon cancer cell line MC-38 submucosally into the colon/rectum of mice. The function of macrophages was studied using clodronate. Finally, single-cell RNA-seq of a previously published dataset in human sporadic cancer was reanalyzed to corroborate these findings. Results: In CAC, Il23r ΔTreg mice had increased tumor size and increased dysplasia compared to WT mice that was associated with decreased tumor-infiltrating macrophages. In the sporadic cancer model, Il23r ΔTreg mice had increased survival and decreased tumor size compared to WT mice. Additionally, MC-38 tumors of Il23r ΔTreg mice exhibited a higher frequency of pro-inflammatory macrophages and IL-17 producing CD4 + T cells. The decreased tumor size in Il23r ΔTreg mice was macrophage-dependent. These data suggest that loss of IL-23R signaling in Treg cells permits IL-17 production by CD4 + T cells that in turn promotes pro-inflammatory macrophages to clear tumors. Finally, analysis of TCGA data and single-cell RNA-seq analysis of a previously published dataset in human sporadic cancer, revealed that IL23R was highly expressed in CRC compared to other cancers and specifically in tumor-associated Treg cells. Conclusion: Inflammation in colorectal carcinogenesis differs with respect to the contribution of IL-23R signaling in regulatory T cells. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Jacobse, Pilat, Li, Brown, Kwag, Buendia, Choksi, Washington, Williams, Markham, Short and Goettel.)
Databáze:	MEDLINE
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