Transcriptional factor EB regulates macrophage polarization in the tumor microenvironment

Abstract

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.

Increased M1 macrophages in young miR‐15a/16−/− mice with tumour grafts or dextran sulphate sodium‐induced colitis

“…P21 regulates macrophage reprogramming by shifting the balance between active p65‐p50 and inhibitory p50‐p50 NF‐κB pathways . The STAT3‐alone activation is generally involved in M2 polarization, particularly in tumour microenvironments . However, the synergistic reaction of NF‐κB and STAT3 is involved with M1 polarization.…”

“…26 The STAT3-alone activation is generally involved in M2 polarization, particularly in tumour microenvironments. 27 However, the synergistic reaction of NF-κB and STAT3 is involved with M1 polarization. In lcn2 −/− 28 and sirt6 −/− 29 mice, LPS stimulation elicits the NF-κB and STAT3 activation for M1 polarization.…”

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

“…30,262 TFEB is one of the regulatory proteins that in cancer cells can become uncoupled from mechanisms that control their cytoplasmic retention. 265 It was shown that TFEB is activated and translocated to the nucleus via inhibition of mammalian target of rapamycin complex by CQ. 263 In vitro, cancer cell autophagy and TFEB activity can be modeled in three-dimensional growth conditions.…”

“…264 In many cell types, though, especially in normal macrophage cells, TFEB is mutually antagonistic to STAT3 activity, and would thereby limit the protection of a tumor by macrophages. 265 It was shown that TFEB is activated and translocated to the nucleus via inhibition of mammalian target of rapamycin complex by CQ. 266 Activation of TFEB by CQ can induce antitumor M1 macrophage activity.…”

Transcriptional regulation of normal human mammary cell heterogeneity and its perturbation in breast cancer

“…Additional reported mechanisms include the altered expression in CAFs of non-coding RNAs and microRNAs (Verghese et al, 2013;Shah et al, 2015;Ren et al, 2018). Other components of the tumor microenvironment, including tumor-associated macrophages, have been implicated in tumor promotion through the expression of TFEB (Fang et al, 2017).…”