Department of Immunology, Biochemistry and Molecular Biology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, Tianjin 300070, China.
Jiangsu Key Laboratory of Phylogenomics and Comparative Genomics, School of Life Sciences, Jiangsu Normal University, Xuzhou, Jiangsu 221116, China.
Aging (Albany NY). 2022 Aug 5;14(15):6149-6168. doi: 10.18632/aging.204208.
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 . 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 -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.
癌症免疫编辑被定义为免疫系统的双重宿主保护和肿瘤促进作用的整合，包括三个阶段：消除、平衡和逃逸。免疫选择压力导致肿瘤细胞丧失主要组织相容性复合体表达或获得免疫抑制基因表达，从而促进肿瘤免疫逃逸和肿瘤进展。白细胞介素-17D（IL-17D）是白细胞介素-17 细胞因子家族的成员，在宿主抗感染和炎症反应中发挥重要作用。然而，IL-17D 在肺癌进展中的作用尚不清楚。在本研究中，我们发现 IL-17D 在人肺癌中高表达，并且增加的 IL-17D 表达与肿瘤分期和总生存时间短有关。IL-17D 过表达显著促进皮下异种移植小鼠模型中的肿瘤生长，但对细胞增殖的影响较小。通过流式细胞术，我们发现 IL-17D 过表达增强了肿瘤相关巨噬细胞向肿瘤微环境的募集。基于过表达 A549 细胞的表达谱，我们发现 IL-17D 通过 MAPK 信号通路增加了巨噬细胞极化和募集相关基因的表达水平。此外，p38 通路的抑制阻断了 IL-17D 诱导的巨噬细胞浸润。这些结果表明，IL-17D 通过 p38 MAPK 信号通路调节肿瘤免疫微环境，提示 IL-17D 可能成为肺癌的潜在治疗靶点。
