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

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

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 3

Expression of Il17a and frequencies of IL-17–producing cells in MC38 tumor from T cell–conditional Il10-knockout mice.

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Expression of Il17a and frequencies of IL-17–producing cells in MC38 tum...
(A) Tumor mass, leukocyte frequency, and FoxP3+ Treg frequencies are similar between WT and Il10–/– mice. (B) Frequencies of CD4+ and CD8+ T cells, and frequencies of IL-17, TNF, or IFN-γ–producing cells following PMA and ionomycin stimulation of MC38 tumor cells from T cell–conditional Il10-knockout mice (Il10T cellΔ/Δ), littermates (Il10fl/fl), Il10–/– mice, or WT mice. Cell frequencies as percentage of leukocytes and mean ± SEM are shown with statistics from 2-tailed Student’s t test with Welch’s correction. (C) Representative contour plot of tumor CD45+CD4+ T cells from FACS analysis used to identify IL-17A+ Th17 cells as quantitated in B. Percentages of gated cells are given. (D) Real-time quantitative PCR for Il17a on whole MC38 tumor tissue from indicated strains of mice. Box-and-whiskers plot is shown with mean ± SEM, n, and P values for mixed-effects ANOVA on combined data from 2 independent experiments (each showing significance).