國家衛生研究院 NHRI:Item 3990099045/10666
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    題名: The c.1085A>G genetic variant of CSF1R gene regulates tumor immunity by altering the proliferation, polarization, and function of macrophages
    作者: Yeh, YM;Hsu, SJ;Lin, PC;Hsu, KF;Wu, PY;Su, WC;Chang, JY;Shen, MR
    貢獻者: National Institute of Cancer Research
    摘要: Purpose: Targeting tumor-associated macrophages with 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 0.1-1 nM 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 10-100 nM 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.
    日期: 2017-10
    關聯: Clinical Cancer Research. 2017 Oct;23(20):6021-6030.
    Link to: http://dx.doi.org/10.1158/1078-0432.ccr-17-1007
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1078-0432&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000413151000004
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85031507392
    顯示於類別:[張俊彥] 期刊論文

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