The introduction of immunosuppressor (TDO inhibitor) significantly improved the efficacy of irinotecan in treating hepat
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ORIGINAL ARTICLE
The introduction of immunosuppressor (TDO inhibitor) significantly improved the efficacy of irinotecan in treating hepatocellular carcinoma Qingqing Liu1,2 · Shixian Hua1,2 · Xinyi Wang1,2 · Feihong Chen1,2 · Shaohua Gou1,2 Received: 16 June 2020 / Accepted: 11 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract 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.
Qingqing Liu and Shixian Hua have contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00262-020-02697-3) contains supplementary material, which is available to authorized users. Extended author information available on the last page of the article
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Cancer Immunology, Immunotherapy
Graphic abstract
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. Keywords Chemo-immunotherapy · Tryptophan-2,3-dioxygenase (TDO) · Irinotecan · Anticancer · Hepatocellular carcinoma
Introduction Liver cancer, the third leading cause of cancer death in the world after lung and stomach cancers, still has not had effective treatments so far, particularly in the later stage [1, 2]. Furthermore, the mortality of primary liver cancer is growing at an alarming rate [3]. Hepatocellular carcinoma (HCC), one of the most common types of primary liver cancers, is a crucial public health issue with low survival rate (about 10%) [4, 5]. The low survival rate of HCC is mainly owing to the risk factors of environment, insufficient diagnosis strategies of the tumor in the early stage, and disappointing drug development [5–7]. Up till now, it is of many difficulties to discover new therapeutic drugs to cure HC
