Interleukin-17D promotes lung cancer progression by inducing tumor-associated macrophage infiltration via the p38 MAPK signaling pathway.

Cancer immunoediting is defined as the integration of the immune system's dual host-protective and tumor-promoting roles, including three phases: elimination, equilibrium, and escape. Immune selective pressure causes tumor cells to lose major histocompatibility complex expression or acquire immunosuppressive gene expression, which promotes tumor immune evasion and tumor progression. Interleukin-17D (IL-17D), a member of the IL-17 family of cytokines, plays an important role in the host defense against infection and inflammation. However, the role of IL-17D in the progression of lung cancer remains unclear. In this study, we found that IL-17D was highly expressed in human lung cancer, and increased IL-17D expression was associated with tumor stage and short overall survival. IL-17D overexpression significantly promoted tumor growth in subcutaneous xenograft mouse models but only slightly affected cell proliferation in vitro. Using flow cytometry, we found that IL-17D overexpression enhances the recruitment of tumor-associated macrophages to the tumor microenvironment. Based on the expression profile of IL17D-overexpressing A549 cells, we found that IL-17D increased the expression levels of macrophage polarization- and recruitment-related genes through the MAPK signaling pathway. Moreover, inhibition of the p38 pathway blocked macrophage infiltration induced by IL-17D. These results suggest that IL-17D regulates the tumor immune microenvironment via the p38 MAPK signaling pathway, highlighting IL-17D as a potential therapeutic target for lung cancer.

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