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Interferon-dependent IL-10 production by Tregs limits tumor Th17 inflammation
C. Andrew Stewart, … , Werner Müller, Giorgio Trinchieri
C. Andrew Stewart, … , Werner Müller, Giorgio Trinchieri
Published October 8, 2013
Citation Information: J Clin Invest. 2013;123(11):4859-4874. https://doi.org/10.1172/JCI65180.
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Research Article Immunology Article has an altmetric score of 13

Interferon-dependent IL-10 production by Tregs limits tumor Th17 inflammation

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Abstract

The capacity of IL-10 and Tregs in the inflammatory tumor microenvironment to impair anticancer Th1 immunity makes them attractive targets for cancer immunotherapy. IL-10 and Tregs also suppress Th17 activity, which is associated with poor prognosis in several cancers. However, previous studies have overlooked their potential contribution to the regulation of pathogenic cancer-associated inflammation. In this study, we investigated the origin and function of IL-10–producing cells in the tumor microenvironment using transplantable tumor models in mice. The majority of tumor-associated IL-10 was produced by an activated Treg population. IL-10 production by Tregs was required to restrain Th17-type inflammation. Accumulation of activated IL-10+ Tregs in the tumor required type I IFN signaling but not inflammatory signaling pathways that depend on TLR adapter protein MyD88 or IL-12 family cytokines. IL-10 production limited Th17 cell numbers in both spleen and tumor. However, type I IFN was required to limit Th17 cells specifically in the tumor microenvironment, reflecting selective control of tumor-associated Tregs by type I IFN. Thus, the interplay of type I IFN, Tregs, and IL-10 is required to negatively regulate Th17 inflammation in the tumor microenvironment. Therapeutic interference of this network could therefore have the undesirable consequence of promoting Th17 inflammation and cancer growth.

Authors

C. Andrew Stewart, Hannah Metheny, Noriho Iida, Loretta Smith, Miranda Hanson, Folkert Steinhagen, Robert M. Leighty, Axel Roers, Christopher L. Karp, Werner Müller, Giorgio Trinchieri

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Figure 5

Ifnar1 and Stat1 are required for expression of IL-10 and Stat1.

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Ifnar1 and Stat1 are required for expression of IL-10 and Stat1.
 
(A) ...
(A) Strategy for identification of CD4+ T cell subsets. Plots show intracellular staining of CD4, FoxP3, and either IL-10, IL-17A, or IFN-γ on single-cell suspensions of MC38 tumors following stimulation with PMA and ionomycin. Percentages of gated cells are given. (B) Frequencies of IL-10+FoxP3+CD4+ T cells, FoxP3+CD4+ T cells, and CD4+ T cells in MC38 tumor are given as percentage of CD4+ T cells or percentage of leukocytes from Ifnar1–/–, Stat1–/–, and WT mice. Mean ± SEM and P values compared with WT are shown for 5 independent experiments combined. (C) Real-time quantitative PCR for Il10 on whole MC38 tumor from Ifnar1–/–, Stat1–/–, and WT mice, normalized to Ptprc (CD45). Box-and-whiskers plots with mean ± SEM, n, and P values compared with WT using combined data from 4 (Ifnar1–/–) or 1 (Stat1–/–) independent experiments.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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