Department of Immunology, Key Laboratory for Experimental Teratology of Ministry of Education, Shandong Provincial Key Laboratory of Infection & Immunology, School of Basic Medical Science, Shandong University, Jinan, Shandong, China.
Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China.
Cancer Res. 2022 Apr 15;82(8):1603-1616. doi: 10.1158/0008-5472.CAN-21-0003.
Macrophages perform key and distinct functions in maintaining tissue homeostasis by finely tuning their activation state. Within the tumor microenvironment, macrophages are reshaped to drive tumor progression. Here we report that tumor necrosis factor α-induced protein 8-like 1 (TIPE1) is highly expressed in macrophages and that depletion of TIPE1 impedes alternative activation of macrophages. TIPE1 enhanced activation of the PI3K/Akt pathway in macrophages by directly binding with and regulating the metabolism of phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3). Accordingly, inhibition of the PI3K/Akt pathway significantly attenuated the effect of TIPE1 on macrophage alternative activation. Tumor-associated macrophages (TAM) in human liver cancer and melanoma tissues showed significantly upregulated TIPE1 expression that negatively correlated with patient survival. In vitro and in vivo, TIPE1 knockdown in macrophages retarded the growth and metastasis of liver cancer and melanoma. Furthermore, blockade or depletion of TGFβ signaling in macrophages abrogated the effects of TIPE1 on tumor cell growth and migration. Together, these results highlight that the phosphoinositide-related signaling pathway is involved in reprogramming TAMs to optimize the microenvironment for cancer progression.
This work provides insight into the fine tuning of macrophage polarization and identifies a potential target for macrophage-based antitumor therapy.
巨噬细胞通过精细调节其激活状态来发挥维持组织内稳态的关键和独特作用。在肿瘤微环境中，巨噬细胞被重塑以促进肿瘤进展。在这里，我们报告肿瘤坏死因子 α 诱导蛋白 8 样 1（TIPE1）在巨噬细胞中高度表达，并且 TIPE1 的耗竭会阻碍巨噬细胞的替代激活。TIPE1 通过直接结合并调节磷脂酰肌醇 4,5-二磷酸（PIP2）和磷脂酰肌醇 3,4,5-三磷酸（PIP3）的代谢，增强了巨噬细胞中 PI3K/Akt 通路的激活。因此，PI3K/Akt 通路的抑制显著减弱了 TIPE1 对巨噬细胞替代激活的作用。人肝癌和黑色素瘤组织中的肿瘤相关巨噬细胞（TAM）显示出明显上调的 TIPE1 表达，其与患者生存呈负相关。在体外和体内，巨噬细胞中 TIPE1 的敲低减缓了肝癌和黑色素瘤的生长和转移。此外，TGFβ 信号在巨噬细胞中的阻断或耗竭消除了 TIPE1 对肿瘤细胞生长和迁移的影响。总之，这些结果强调了磷酸肌醇相关信号通路参与了重编程 TAMs 以优化癌症进展的微环境。
这项工作深入了解了巨噬细胞极化的精细调控，并确定了一个基于巨噬细胞的抗肿瘤治疗的潜在靶点。
