國家衛生研究院 NHRI:Item 3990099045/14680
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    题名: A G-quadruplex stabilizer, CX-5461 combined with two immune checkpoint inhibitors enhances in vivo therapeutic efficacy by increasing PD-L1 expression in colorectal cancer
    作者: Chung, SY;Chang, YC;Hsu, DS;Hung, YC;Lu, ML;Hung, YP;Chiang, NJ;Yeh, CN;Hsiao, M;Soong, J;Su, Y;Chen, MH
    贡献者: National Institute of Cancer Research
    摘要: PURPOSE: Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy can improve the limited efficacy of colorectal cancer (CRC) immunotherapy. CX-5461 causes substantial DNA damage and genomic instability and can increase ICIs' therapeutic efficacies through tumor microenvironment alteration. RESULTS: We analyzed whether CX-5461 enhances ICIs' effects in CRC and discovered that CX-5461 causes severe DNA damage, including cytosolic dsDNA appearance, in various human and mouse CRC cells. Our bioinformatics analysis predicted CX-5461-based interferon (IFN) signaling pathway activation in these cells, which was verified by the finding that CX-5461 induces IFN-α and IFN-β secretion in these cells. Next, cGAMP, phospho-IRF3, CCL5, and CXCL10 levels exhibited significant posttreatment increases in CRC cells, indicating that CX-5461 activates the cGAS-STING-IFN pathway. CX-5461 also enhanced PD-L1 expression through STAT1 activation. CX-5461 alone inhibited tumor growth and prolonged survival in mice. CX-5461+anti-PD-1 or anti-PD-L1 alone exhibited synergistic growth-suppressive effects against CRC and breast cancer. CX-5461 alone or CX-5461+anti-PD-1 increased cytotoxic T-cell numbers and reduced myeloid-derived suppressor cell numbers in mouse spleens. CONCLUSIONS: Therefore, clinically, CX-5461 combined with ICIs for CRC therapy warrants consideration because CX-5461 can turn cold tumors into hot ones.
    日期: 2023-01
    關聯: Neoplasia. 2023 Jan;35:Article number 100856.
    Link to: http://dx.doi.org/10.1016/j.neo.2022.100856
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1476-5586&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000892216500004
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85142697545
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