期刊
ONCOIMMUNOLOGY
卷 9, 期 1, 页码 -出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2020.1774281
关键词
Macrophage; NK cells; PDK1; macrophage polarization; mTOR
资金
- National Natural Science Foundation of China [81725007, 31830027, 31821003, 91942308]
- National Key Research & Developmental Program of China [2018YFC1003900]
- Beijing Natural Science Foundation [5172018, 7184218]
- Beijing Municipal Administration of Hospital Clinical Medicine Development of Special Funding Support [ZYLX201802]
A large number of heterogeneous macrophages can be observed in solid tumor lesions. Classically activated M1 macrophages are a powerful killer of cancer cells. In contrast, tumor-associated macrophages (TAMs) are often referred to as M2 phenotype and usually impair tumor immunity mediated by cytotoxic lymphocytes, natural killer (NK) cells and CD8(+)T cells. Therefore, orchestrating M2 to M1 reprogramming will provide a promising approach to tumor immunotherapy. Here we used a PyMT-induced spontaneous breast cancer model in which M2-polarized macrophages were abundant. This M2 phenotype was closely related to tumor progression and immune dysfunction of NK cells and CD8(+)T cells. We then found that these TAMs showed increased energy expenditure and over-activation of two kinases, Akt and mammalian target of rapamycin (mTOR). Myeloid inactivation of phosphoinositide-dependent kinase-1 (PDK1), the upstream regulator for Akt and mTOR signaling, significantly reduced excessive metabolic activation of macrophages. Notably, the loss of PDK1 significantly led to regression of breast cancer and prevented lung metastasis. Mechanistically, PDK1 deficiency mainly inhibited the activation of mTOR complex 1 (mTORC1), transforming TAMs into M1 phenotype, thereby reversing tumor-related dysfunction of T cells and NK cells. Therefore, targeting PDK1 may be a new approach for M2 macrophage-enriched solid tumor immunotherapy.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据