The c.1085A>G Genetic Variant of <i>CSF1R</i> Gene Regulates Tumor Immunity by Altering the Proliferation, Polarization, and Function of Macrophages.

Abstract

<b>Purpose:</b> 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 <i>CSF1R</i> germline genetic variant on CSF-1R signaling and the susceptibility to CSF-1R inhibitors.<b>Experimental designs:</b><i>CSF1R</i> 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.<b>Results:</b> A <i>CSF1R</i> 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, <i>CSF1R</i> genetic variant was significantly associated with disease-free survival in colorectal, endometrial, and ovarian cancer. In terms of differentiation, macrophages with <i>CSF1R</i> 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 <i>CSF1R</i> 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.<b>Conclusions:</b> The <i>CSF1R</i> 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. <i>Clin Cancer Res; 23(20); 6021-30. ©2017 AACR</i>.