Tumor immune escape plays a critical role in malignant tumor progression and leads to the failure of anticancer immunotherapy. Spi-B, a lymphocyte lineage-specific Ets transcription factor, participates in mesenchymal invasion and favors metastasis in human lung cancer. However, the mechanism through which Spi-B regulates the tumor immune environment has not been elucidated. In this study, we demonstrated that Spi-B enhanced the infiltration of tumor-associated macrophages (TAMs) in the tumor microenvironment using subcutaneous mouse models and clinical samples of human lung cancer. Spi-B overexpression increased the expression of TAM polarization- and recruitment-related genes, including CCL4. Moreover, deleting CCL4 inhibited the ability of Spi-B promoting macrophage infiltration. These data suggest that Spi-B promotes the recruitment of TAMs to the tumor microenvironment via upregulating CCL4 expression, which contributes to the progression of lung cancer.
Cancer immunoediting is defined as the integration of the immune system's dual host-protective and tumorpromoting 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 recruitmentrelated 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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