The introduction of immunosuppressor (TDO inhibitor) significantly improved the efficacy of irinotecan in treating hepatocellular carcinoma.

As TDO inhibitors can improve the efficacy of tumor chemotherapeutics, two TDO-targeted conjugates consisting of irinotecan (Ir) and a TDO inhibitor unit were designed and prepared to reverse tumor immune suppression, which could remarkably enhance antitumor activity of Ir by boosting cellular uptakes against TDO overexpressed HepG2 cancer cells. In vitro mechanistic studies demonstrated that compound PVIS-Ir and PVIG-Ir could arrest cell cycle at G2 phase and induce cell apoptosis by mitochondrial apoptotic pathway. Furthermore, compound PVIS-Ir could effectively inhibit TDO protein expression via releasing a TDO inhibitor derivative, which could also completely embed in TDO protein pocket. Further mechanism study indicated that PVIS-Ir could block kynurenine production and deactivate aryl hydrocarbon receptor (AHR), resulting in T-cell activation and proliferation. In vivo studies confirmed that PVIS-Ir could improve tumor immune microenvironment in a murine model. This combinational strategy of chemotherapy and immunotherapy can be a promising way in the treatment of hepatocellular carcinoma. Conjugates obtained by combining an immune checkpoint TDO inhibitor with irinotecan via different linkers could improve tumor immune microenvironment by inhibiting the TDO enzyme expression to block kynurenine production and induce HepG2 cancer cell apoptosis via DNA damage through releasing a TDO inhibitor and irinotecan in cancer cells.

Citation

Qingqing Liu, Shixian Hua, Xinyi Wang, Feihong Chen, Shaohua Gou. The introduction of immunosuppressor (TDO inhibitor) significantly improved the efficacy of irinotecan in treating hepatocellular carcinoma. Cancer immunology, immunotherapy : CII. 2021 Feb;70(2):497-508

Mesh Tags

Substances

PMID: 32840656

search → result