Colony-Stimulating Factor 1 Receptor Blockade Inhibits Tumor Growth by Altering the Polarization of Tumor-Associated Macrophages in Hepatocellular Carcinoma

Abstract

Colony-stimulating factor-1 (CSF-1) and its receptor, CSF-1R, regulate the differentiation and function of macrophages and play an important role in macrophage infiltration in the context of hepatocellular carcinoma (HCC). The therapeutic effects of CSF-1R blockade in HCC remain unclear. In this study, we found that CSF-1R blockade by PLX3397, a competitive inhibitor with high specificity for CSF-1R tyrosine kinase, significantly delayed tumor growth in mouse models. PLX3397 inhibited the proliferation of macrophages in vitro, but intratumoral macrophage infiltration was not decreased by PLX3397 in vivo. Gene expression profiling of tumor-associated macrophages (TAMs) showed that TAMs from the PLX3397-treated tumors were polarized toward an M1-like phenotype compared with those from vehicle-treated tumors. In addition, PLX3397 treatment increased CD8 + T-cell infiltration, whereas CD4 + T-cell infiltration was decreased. Further study revealed that tumor cell-derived CSF-2 protected TAMs from being depleted by PLX3397. In conclusion, CSF-1R blockade delayed tumor growth by shifting the polarization rather than the depletion of TAMs. CSF-1R blockade warrants further investigation in the treatment of HCC.on May 9, 2018.

The emerging roles of macrophages in cancer metastasis and response to chemotherapy

“…111,179,192 Furthermore, recent studies have collectively shown that macrophage repolarization in the tumor microenvironment can be achieved by inhibition of the CSF1/CSF1R signaling pathway, and is associated with phenotypic modifications such as activation/enhancement of CD8 + T-cell mediated immunity and suppression of the angiogenic potential. [197][198][199] This evidence may indicate that the TAMs described in this review are not terminally polarized, but subjected to repolarization dependent on contextual cues from the tumor microenvironment. Also, therapeutic intervention seems to also be a viable possibility.…”

“…Indeed, despite the original thought that TIE2 + macrophages may either arise as tissue‐resident macrophages, or from committed TIE2 + monocyte progenitors, there is now strong evidence that hypoxia stimulates TIE2 expression . Furthermore, recent studies have collectively shown that macrophage repolarization in the tumor microenvironment can be achieved by inhibition of the CSF1/CSF1R signaling pathway, and is associated with phenotypic modifications such as activation/enhancement of CD8 + T‐cell mediated immunity and suppression of the angiogenic potential . This evidence may indicate that the TAMs described in this review are not terminally polarized, but subjected to repolarization dependent on contextual cues from the tumor microenvironment.…”

Nonresolving macrophage‐mediated inflammation in malignancy

“…The results from preclinical models of CSF‐1R kinase inhibition are both surprising and confusing. Several studies have reported that CSF‐1R inhibitors do not overtly deplete macrophages (or microglia, which are dependent on IL‐34, a cytokine that also binds the CSF‐1R) but instead changes their polarization status . One explanation for the lack of macrophage depletion in this system was the increased local production of GM‐CSF .…”

Immune landscape of hepatocellular carcinoma microenvironment: Implications for prognosis and therapeutic applications

“…105 CSF1R blockade by PLX3397, a competitive inhibitor, has been shown to delay tumour growth in mouse models. 106 This effect is accompanied by a phenotypic shift of macrophages towards M1 pro-inflammatory type rather than by a decrease in macrophage infiltration, and by an increase of CD8 + T cell multiplicity in tumour tissue. These observations warrant further investigation of CSF1R blockade as a therapeutic approach for human HCC.…”

“…Colony Stimulating Factor 1 (CSF1) attracts macrophages to the HCC microenvironment, stimulating their differentiation to a pro‐tumorigenic phenotype . CSF1R blockade by PLX3397, a competitive inhibitor, has been shown to delay tumour growth in mouse models . This effect is accompanied by a phenotypic shift of macrophages towards M1 pro‐inflammatory type rather than by a decrease in macrophage infiltration, and by an increase of CD8 + T cell multiplicity in tumour tissue.…”