Fang Liang, Hodge Johnie, Saaoud Fatma, Wang Junfeng, Iwanowycz Stephen, Wang Yuzhen, Hui Yvonne, Evans Trent D, Razani Babak, Fan Daping
Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA.
Department of Immunology, Fourth Military Medical University, Xi'an, China.
Oncoimmunology. 2017 Apr 20;6(5):e1312042. doi: 10.1080/2162402X.2017.1312042. eCollection 2017.
Tumor microenvironment (TME) contains a variety of infiltrating immune cells. Among them, tumor-associated macrophages (TAMs) and their alternative activation contribute greatly to the progression of tumors. The mechanisms governing macrophage polarization in the TME are unclear. Here, we show that in TAMs or macrophages under tumor-conditioned medium treatment, the expression of transcription factor EB (TFEB) is reduced and more of the TFEB protein is in an inactive cytosolic form. Transforming growth factor (TGF)-β is identified as a main driving force for the reduced TFEB expression and activity in TAMs via activating ERK signaling. TFEB interference in macrophages significantly enhanced their alternative activation, with reduced expression of MHC-II and co-stimulatory molecule CD80, decreased ability to activate T cells, and increased ability to attract tumor cells. When co-inoculated with tumor cells, macrophages with TFEB knockdown significantly enhanced tumor growth with increased infiltration of M2-like macrophages, reduced infiltration of CD8 T cells, and enhanced angiogenesis in the tumors. Mechanistic studies revealed that TFEB downregulation resulted in macrophage M2 polarization through reducing SOCS3 production and enhancing STAT3 activation. We further demonstrate that the activation of TFEB by hydroxypropyl-β-cyclodextrin in macrophages suppressed their M2 polarization and tumor-promoting capacity, and that macrophage-specific TFEB overexpression inhibited breast tumor growth in mice. Therefore, our data suggest that TFEB plays critical roles in macrophage polarization, and the downregulation of TFEB expression and activation is an integral part of tumor-induced immune editing in the TME. This study provides a rationale for a new cancer treatment strategy by modulating macrophage polarization through activating TFEB.
肿瘤微环境（TME）包含多种浸润性免疫细胞。其中，肿瘤相关巨噬细胞（TAM）及其替代性激活在肿瘤进展中起很大作用。TME中巨噬细胞极化的调控机制尚不清楚。在此，我们表明，在TAM或经肿瘤条件培养基处理的巨噬细胞中，转录因子EB（TFEB）的表达降低，且更多的TFEB蛋白处于无活性的胞质形式。转化生长因子（TGF）-β被确定为通过激活ERK信号传导降低TAM中TFEB表达和活性的主要驱动力。巨噬细胞中的TFEB干扰显著增强了它们的替代性激活，导致MHC-II和共刺激分子CD80表达降低、激活T细胞的能力下降以及吸引肿瘤细胞的能力增加。当与肿瘤细胞共同接种时，敲低TFEB的巨噬细胞显著增强肿瘤生长，同时M2样巨噬细胞浸润增加、CD8 T细胞浸润减少以及肿瘤血管生成增强。机制研究表明，TFEB下调通过减少SOCS3产生和增强STAT3激活导致巨噬细胞M2极化。我们进一步证明，羟丙基-β-环糊精在巨噬细胞中激活TFEB可抑制其M2极化和肿瘤促进能力，并且巨噬细胞特异性TFEB过表达可抑制小鼠乳腺肿瘤生长。因此，我们的数据表明TFEB在巨噬细胞极化中起关键作用，TFEB表达和激活的下调是TME中肿瘤诱导的免疫编辑的一个组成部分。本研究为通过激活TFEB调节巨噬细胞极化的新癌症治疗策略提供了理论依据。
