The Influence Of Feiji Recipe And Astragaloside IV On IDO And Immune Escape In Tumor Microenvironment

One mechanism of immune escape in tumor microenvironment is elevation of the tryptophan-catabolizing enzyme, indoleamine-2,3-dioxygenase (IDO). It is involved in tumor escape by tryptophan exhausting or kynurenine accumulating and may be a new target of cancer therapy. The efficacy of immunotherapy for lung cancer isn’t entirely satisfactory because of peculiar histological type and immunosuppressive microenvironment of lung cancer. Astragaloside IV (AS-IV) is an active component and monomer of Feiji Recipe, which has been shown to be capable of stabilizing disease, improving quality of life as well as inhibiting lung tumor growth and metastasis.In this study, we used IDO overexpressed murine Lewis lung carcinoma cells (2LL) to establish an orthotopic lung cancer model, and investigated the expressing rules of IDO and its metabolites in lung cancer microenvironment and peripheral blood systematically by RT-PCR, Western blot, flow cytometry and HPLC. Meanwhile, we observed T cell functions in cancer microenvironment. In vivo study we showed the inhibiting effect of Feiji Recipe and AS-IV on IDO expression in tumor microenvironment and the levels of cytokines in peripheral blood.Our results showed that IDO overexpressed orthotopic lung cancer models had poorer quality of life and immunity comparing with healty mice. Feiji Recipe and AS-IV could improve immunity and promote proliferation of lymphocytes. Overexpression of IDO in tumor microenvironment could induce dysfunction of immune cells, while Feiji Recipe and AS-IV could improve cellular immune function by down-regulating the percentage of Tregs and up-regulating CTLs. In Feiji Recipe and AS-IV groups, the expression and enzymatic activity of IDO was significantly decreased, suggesting that immunomodulation functions of Feiji Recipe and AS-IV were related to IDO. Consistent with their ability to interfere with T-cell immunity, Feiji Recipe and AS-IV could not only block immune checkpoint CTLA-4 and PD-1/PD-L1 through inhibiting PI3K-Akt pathway activation, but also increase the levels of IFN-y, IL-2 and IL-1 and suppress VEGF, TGF-β,IL-6 and IL-10 expression.These results revealed the mechanism of Feiji Recipe and AS-IV in cancer therapy, and provide new experimental evidences of IDO-targeted immunotherapy.