The Taming of the TAMs.

Tumor-associated macrophages and microglia (TAMs) are considered crucial elements in cancer progression. Recent work reveals the molecular mechanisms underlying acquired resistance to colony-stimulating factor-1 receptor (CSF-1R) inhibitors in glioblastoma (GBM) and shows that targeting TAMs with CSF-1R inhibitors leads to an antitumor response in GBM followed by the acquisition of resistance to treatment through the induction of insulin-like growth factor 1 (IGF-1) expression in TAMs.

Seoane J 《-》

CSF-1R inhibition alters macrophage polarization and blocks glioma progression.

Pyonteck SM ，Akkari L ，Schuhmacher AJ ，Bowman RL ，Sevenich L ，Quail DF ，Olson OC ，Quick ML ，Huse JT ，Teijeiro V ，Setty M ，Leslie CS ，Oei Y ，Pedraza A ，Zhang J ，Brennan CW ，Sutton JC ，Holland EC ，Daniel D ，Joyce JA ... -  《-》

The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas.

Macrophages accumulate with glioblastoma multiforme (GBM) progression and can be targeted via inhibition of colony-stimulating factor-1 receptor (CSF-1R) to regress high-grade tumors in animal models of this cancer. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. We show that although overall survival is significantly prolonged, tumors recur in >50% of mice. Gliomas reestablish sensitivity to CSF-1R inhibition upon transplantation, indicating that resistance is tumor microenvironment-driven. Phosphatidylinositol 3-kinase (PI3K) pathway activity was elevated in recurrent GBM, driven by macrophage-derived insulin-like growth factor-1 (IGF-1) and tumor cell IGF-1 receptor (IGF-1R). Combining IGF-1R or PI3K blockade with CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors.

Quail DF ，Bowman RL ，Akkari L ，Quick ML ，Schuhmacher AJ ，Huse JT ，Holland EC ，Sutton JC ，Joyce JA ... -  《-》

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

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. The therapeutic effects of CSF-1R blockade in hepatocellular carcinoma 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 (TAM) 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 hepatocellular carcinoma. Mol Cancer Ther; 16(8); 1544-54. ©2017 AACR.

Ao JY ，Zhu XD ，Chai ZT ，Cai H ，Zhang YY ，Zhang KZ ，Kong LQ ，Zhang N ，Ye BG ，Ma DN ，Sun HC ... -  《-》

Preclinical evaluation of 3D185, a novel potent inhibitor of FGFR1/2/3 and CSF-1R, in FGFR-dependent and macrophage-dominant cancer models.

Peng X ，Hou P ，Chen Y ，Dai Y ，Ji Y ，Shen Y ，Su Y ，Liu B ，Wang Y ，Sun D ，Jiang Y ，Zha C ，Xie Z ，Ding J ，Geng M ，Ai J ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》