DC-derived IL-27 suppresses anti-tumor immunity via the modulation of gut microbiota

Background: Chronic inflammation has been shown to be crucial in promoting tumor initiation and development in many cancer types, including hepatocellular carcinoma (HCC). It is characterized by the persistent expression of inflammatory cytokines surrounding the tissues. IL-27 is a heterodimeric cytokine that consists of EBI3 and p28, which can be expressed by many antigen presenting cells, including monocytes, macrophages, and dendritic cells (DCs). The role of IL-27 in tumor development is controversial. Gut microbiota plays an important role in immune system development and homeostasis, while how it can be regulated to impact anti-tumor immune response is poorly understood. Results: We demonstrated a tumor-promoting role of DC-derived IL-27 via the modulation of gut microbiota in murine models. IL-27p28 DC-conditional knockout (Itgax-IL-27p28 f/f ) mice exhibited reduced tumor growth compared with WT controls. T cell anti-tumor response was enhanced, and inhibitory receptor expression was decreased. Interestingly, when WT mice received fecal transplant from Itgax-IL-27p28 f/f mice, tumor growth was significantly inhibited. Their gut microbiota exhibited distinct features and gavage of bifidobacterium, a bacteria strain that was greatly increased in Itgax-IL-27p28 f/f mice, reduced tumor growth. Furthermore, MHC class II expression on tumor necrosis factor and inducible nitric-oxide-synthase-producing DCs (TIP-DCs) was increased in Itgax-IL-27p28 f/f mice, and their activation could be inhibited by the gut microbiota modulated by IL-27. Their function of activating CD8 + T cells was also enhanced in the absence of DC-derived IL-27. Conclusion: DC-derived IL-27 could promote tumor development and suppress anti-tumor immune response by inhibiting the function of TIP-DCs via the modulation of gut microbiota. This indirect effect of IL-27 on adaptive immune response provides insights into possible organ-specific functions of IL-27 and targeting IL-27 in tumor immunotherapy.