Interferon-dependent IL-10 production by Tregs limits tumor Th17 inflammation.
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.
C Andrew
CA
Stewart
Hannah
H
Metheny
Noriho
N
Iida
Loretta
L
Smith
Miranda
M
Hanson
Folkert
F
Steinhagen
Robert M
RM
Leighty
Axel
A
Roers
Christopher L
CL
Karp
Werner
W
Müller
Giorgio
G
Trinchieri
D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects; D007249:Inflammation / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control; D007370:Interferon Type I / Q000378:metabolism*; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology*
C508609:IL10 protein, human; C556062:IL10 protein, mouse; C508032:Ifnar1 protein, mouse; C098680:Il17a protein, mouse; D007370:Interferon Type I; D020381:Interleukin-17; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D016753:Interleukin-10; D053633:Receptor, Interferon alpha-beta