IL-17 can promote tumor growth through an IL-6–Stat3 signaling pathway

Although the Th17 subset and its signature cytokine, interleukin (IL)-17A (IL-17), are implicated in certain autoimmune diseases, their role in cancer remains to be further explored. IL-17 has been shown to be elevated in several types of cancer, but how it might contribute to tumor growth is still unclear. We show that growth of B16 melanoma and MB49 bladder carcinoma is reduced in IL-17−/− mice but drastically accelerated in IFN-γ−/− mice, contributed to by elevated intratumoral IL-17, indicating a role of IL-17 in promoting tumor growth. Adoptive transfer studies and analysis of the tumor microenvironment suggest that CD4+ T cells are the predominant source of IL-17. Enhancement of tumor growth by IL-17 involves direct effects on tumor cells and tumor-associated stromal cells, which bear IL-17 receptors. IL-17 induces IL-6 production, which in turn activates oncogenic signal transducer and activator of transcription (Stat) 3, up-regulating prosurvival and proangiogenic genes. The Th17 response can thus promote tumor growth, in part via an IL-6–Stat3 pathway

Oxysterol gradient generation by lymphoid stromal cells guides activated B cell movement during humoral responses

7α,25-dihydroxycholesterol (7α,25-OHC) was recently identified as an EBI2(GPR183) ligand; however, the cellular sources of this oxysterol are undefined. 7α,25-OHC is synthesized from cholesterol by the stepwise actions of CH25H and CYP7B1, and is further metabolized to a 3-oxo derivative by HSD3B7. We show that CYP7B1 and HSD3B7 control EBI2-ligand concentration in lymphoid tissues. CH25H and CYP7B1 are abundant at the B cell follicle perimeter whereas HSD3B7 is abundant in the T zone. Lymphoid stromal cells are the main EBI2-ligand producers and also mediate ligand inactivation. Dendritic cell-HSD3B7 is additionally needed to keep T zone ligand concentrations low and to aid activated B cell positioning. CYP7B1-deficiency results in defective plasma cell responses. These findings establish that CYP7B1 and HSD3B7 have essential roles in controlling oxysterol production outside the liver and they suggest multiple lymphoid resident cells cooperate to form the 7α,25-OHC gradients required for B cell responses