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Distinct roles for interleukin-23 receptor signaling in regulatory T cells in sporadic and inflammation-associated carcinogenesis.
Jacobse, Justin; Pilat, Jennifer M; Li, Jing; Brown, Rachel E; Kwag, Aaron; Buendia, Matthew A; Choksi, Yash A; Washington, M Kay; Williams, Christopher S; Markham, Nicholas O; Short, Sarah P; Goettel, Jeremy A.
Afiliación
  • Jacobse J; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States.
  • Pilat JM; Department of Pediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, Netherlands.
  • Li J; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States.
  • Brown RE; Department of Medicine, Veterans Affairs Tennessee Valley Healthcare System, 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; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United States.
  • Choksi YA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States.
  • Washington MK; Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United States.
  • Williams CS; Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, TN, United States.
  • Markham NO; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States.
  • Short SP; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Monroe Carell Jr. Children's Hospital at Vanderbilt, 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.
Front Oncol ; 13: 1276743, 2023.
Article en En | MEDLINE | ID: mdl-38375204
ABSTRACT

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.
Palabras clave

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Idioma: En Revista: Front Oncol Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Idioma: En Revista: Front Oncol Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos