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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
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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Neoplasia Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9709093/ https://www.ncbi.nlm.nih.gov/pubmed/36442297 http://dx.doi.org/10.1016/j.neo.2022.100856 |
Sumario: | 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. |
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