Critical Role of Dendritic Cell–Derived IL-27 in Antitumor Immunity through Regulating the Recruitment and Activation of NK and NKT Cells

Abstract

Critical roles of IL-27 in autoimmune diseases and infections have been reported; however, the contribution of endogenous IL-27 to tumor progression remains elusive. In this study, by using IL-27p28 conditional knockout mice, we demonstrate that IL-27 is critical in protective immune response against methyl-cholanthrene–induced fibrosarcoma and transplanted B16 melanoma, and dendritic cells (DCs) are the primary source. DC-derived IL-27 is required for shaping tumor microenvironment by inducing CXCL-10 expression in myeloid-derived suppressor cells and regulating IL-12 production from DCs, which lead to the recruitment and activation of NK and NKT cells resulting in immunological control of tumors. Indeed, reconstitution of IL-27 or CXCL-10 in tumor site significantly inhibits tumor growth and restores the number and activation of NK and NKT cells. In summary, our study identifies a previous unknown critical role of DC-derived IL-27 in NK and NKT cell–dependent antitumor immunity through shaping tumor microenvironment, and sheds light on developing novel therapeutic approaches based on IL-27.

A requirement of dendritic cell-derived interleukin-27 for the tumor infiltration of regulatory T cells

“…WT, EIIa-p28 f/f , and Itgax-p28 f/f mice were transplanted with B16 melanoma cells, and Tregs (Foxp3 ϩ CD4 ϩ ) in tumor tissues were examined. Although we demonstrated recently that endogenous IL-27 inhibited tumor growth in a NK1.1 ϩ celldependent manner [12], surprisingly, we found that tumorpromoting Tregs were substantially decreased selectively in tumor sites in the B16 melanoma model in the absence of hostderived IL-27, whereas no significant changes were noticed in the spleen of tumor-bearing mice ( Fig. 1A-C).…”

“…4D). Although our previous study proved that IL-27 was able to induce the expression of another chemokine-CXCL-10 -in MDSCs [12], IL-27 failed to induce a substantial amount of CCL22 in MDSCs (Fig. 4D), which indicated that the induction of CCL22 by IL-27 might be restricted in tumor-associated DCs.…”

“…Whereas IL-27 amplifies TGF-␤-induced Foxp3 expression in vitro [20], other work has debated that it could limit the Treg population in vivo by suppressing Foxp3 induction directly [21] or through suppressing IL-2 indirectly [22]; thus, the function of IL-27 might be context-dependent. Our recent published work established that in the absence of DC-derived IL-27, the recruitment and function of NK and NKT cells in the tumor microenvironment were impaired significantly and rendered mice more susceptible to tumor growth [12]; however, its impact on Tregs in the tumor microenvironment was not elucidated.…”

The Immunobiology of Interleukin-27

“…For example, IL-17 has a key role in promoting neutrophil responses, and IL-27 can inhibit innate NK and γδ T cell production of IL-17 (151,152), an activity that could contribute to control of neutrophil responses. Additionally, there have been reports that IL-27 blocks the proinflammatory activities of NKT cells in a model of hepatitis (30), but it can activate NK and NKT activities to promote antitumor responses and to secrete IL-10 (153,154). This literature emphasizes that many lymphocyte populations associated with innate immunity (NK, NKT, γδ T cells) are sensitive to IL-27, but little is known about whether any of the emerging populations of innate lymphoid cells associated with barrier function are influenced by IL-27.…”

Interleukin-27 and IFNγ regulate the expression of CXCL9, CXCL10, and CXCL11 in hepatitis

“…IL-27 induced STAT1-dependent response in hepatic tissue (hepatoma cell line and in hepatocytes) by regulating IFNγ-related gene expression [25]. The increased level of IL-27 was associated with HBV infection in human patients and in vitro studies [26], and IL-27 directly activated the anti-viral/tumor NK and NKT cells [27]. We previously demonstrated the involvement of IL-27 in T cell-mediated hepatitis induced by concanavalin A (ConA) [23] in which liver injury is mediated by NK and T/NKT cells with over-expression of different inflammatory cytokines and chemokines [28][29][30][31].…”