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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

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 1

Tumor Tregs are a predominant source of Il10.

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Tumor Tregs are a predominant source of Il10.
 
(A and C) Expression of ...
(A and C) Expression of IL-10eGFP in leukocyte populations (A) and CD4+ T cells (C) from MC38 tumor grown in VERT-X mice (black line) or B6 WT (gray) mice. Statistics show percentage of cells in each quadrant for 1 representative experiment of 3 or more. (B) Definition of tumor CD4+ Tregs by intracellular staining of FoxP3 (black line) or isotype (gray) staining. Percentage of gated cells is shown. (D) Real-time quantitative PCR for Il10 on sorted cell populations from MC38 tumor, normalized to Hprt. Experiment is representative of 3. (E) Il10 expression in MC38 tumor from T cell–conditional Il10-knockout mice (Il10T cellΔ/Δ). RNA was extracted from unprocessed MC38 tumors from indicated strains of mice and real-time quantitative PCR performed for Il10. Relative expression of Il10 to Hprt is shown in a box-and-whiskers plot (ND, not detected). Data were combined from 2 independent experiments and statistical analysis performed by mixed-effects ANOVA (Tukey-Kramer). Mean ± SEM and n are also shown.

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