Abstract
Purpose: Targeting tumor-associated macrophages with colony-stimulating factor 1 receptor (CSF-1R) inhibition reveals a strategy for cancer therapy. Here, we studied the impact of CSF1R germline genetic variant on CSF-1R signaling and the susceptibility to CSF-1R inhibitors.Experimental designs:CSF1R germline genetic variants were studied in 140 cancer patients. CSF-1R phosphorylation, endocytosis, and macrophage polarization were measured as the response to CSF-1 stimulation. Tumor-associated macrophages in surgical specimens and sensitivity to CSF-1R inhibitors were used to determine macrophage function.Results: A CSF1R c.1085A>G genetic variant causing the change of histidine to arginine in the domain of receptor dimerization was identified as a high allele frequency in Eastern Asian population. Cancer patients with this variant allele had less M2-like tumor-associated macrophages accompanied by low VEGF expression in tumor tissues. Importantly, CSF1R genetic variant was significantly associated with disease-free survival in colorectal, endometrial, and ovarian cancer. In terms of differentiation, macrophages with CSF1R c.1085A>G genetic variant displayed a refractory response to CSF-1 stimulation and macrophage survival was sensitive to CSF-1R inhibitors with IC50 of 0.1 to 1 nmol/L range. On contrast, CSF-1 induced a prominent phosphorylation and rapid endocytosis of CSF-1R, leading to an M2-like dominant polarization in macrophages with CSF1R c.1085 genotype A_A, in which CSF-1R inhibitors of PLX3397, BLZ945, and GW2580 inhibited macrophage survival with IC50 of 10 to 100 nmol/L range.Conclusions: The CSF1R c.1085A>G genetic variant regulates tumor immunity by altering the polarization and function of macrophages. This genetic variant confers the sensitivity to CSF-1R inhibitors, implying as a biomarker in targeting CSF-1R signaling for cancer treatment. Clin Cancer Res; 23(20); 6021-30. ©2017 AACR.
Highlights
Colony stimulating factor 1 receptor (CSF-1R) is the receptor for CSF-1, a cytokine that controls the production, differentiation, and function of macrophages (1)
Macrophages with CSF1R c.1085A>G genetic variant displayed a refractory response to CSF-1 stimulation and macrophage survival was sensitive to CSF-1R inhibitors with IC50 of 0.1 to 1 nmol/L range
The CSF1R c.1085A>G genetic variant regulates tumor immunity by altering the polarization and function of macrophages. This genetic variant confers the sensitivity to CSF-1R inhibitors, implying as a biomarker in targeting CSF-1R signaling for cancer treatment
Summary
Colony stimulating factor 1 receptor (CSF-1R) is the receptor for CSF-1, a cytokine that controls the production, differentiation, and function of macrophages (1). Exposure of macrophages to granulocyte/macrophage colony-stimulating factor (GM-CSF) leads to an M1-like state that produces the pro-inflammatory cytokines, such as tumor necrosis factor (TNF), IL6, and IL12, whereas exposure to CSF-1 leads macrophages to be maintained in an M2-like polarized state (2). The M2-like macrophages produce cytokines that could promote tumor progression, angiogenesis, and matrix remodeling. Tumor-associated macrophages are often found to have M2-like phenotype that is associated with a poor outcome in different types of cancers (3). Targeting CSF-1R signaling by monoclonal antibody or small molecular inhibitors to manipulate macrophage function has been studied in the treatment of cancer, such as glioma (4), breast cancer (5), and pancreatic cancer (6). Different responses to CSF-1R inhibition are observed in the early-phase clinical trials and several clinical studies of immunotherapy are undergoing to evaluate the combination of CSF-1R inhibition and blockade of PD-1/PD-L1 (7)
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