The role of TFEB in tumor-associated macrophages

Abstract

Abstract Alternatively activated (M2-like) tumor-associated macrophages (TAMs) have been shown to promote immune suppression, invasion, angiogenesis, the establishment of distant metastases, and maintain the breast cancer stem cell population. However, the mechanisms governing TAM polarization are not fully understood. Transcription factor EB (TFEB) has been recently investigated due to its role as the master regulator of autophagy, but little is known regarding its role in governing macrophage activation or other immune response pathways. We show here that TFEB transcription and activation are reduced in TAMs, and TGF-β-induced activation of ERK signaling is the driving force behind this phenomenon. siRNA knockdown of TFEB in macrophages significantly enhances their alternative activation. Co-inoculation of these macrophages with breast tumor cells results in an increase of both tumor growth and infiltration of M2-like TAMs. Further mechanistic studies reveal that TFEB knockdown regulates M2 polarization by decreasing activation of SOCS3, which acts as an inhibitor of STAT3. These findings led us to further investigate whether increasing TFEB activation in TAMs could decrease their alternative activation and their tumor promoting properties. We found that activation of macrophage TFEB suppresses alternative activation, and introduction of these macrophages at the time of tumor initiation decreases tumor growth in multiple murine models. Therefore, our data demonstrate that the downregulation of TFEB is an integral part of immune editing in the tumor microenvironment, and provides a rationale for a new cancer treatment strategy involving the modulation of TAM polarization through activating TFEB.