Indoleamine 2,3-dioxygenase-1 (IDO) is an immune-regulatory enzyme expressed by most human tumors. IDO expression by tumor cells and the cells of the tumor microenvironment induces anergy and apoptosis in tumor-infiltrating NK cells, CD4+ and CD8+ T cells. IDO-mediated immune suppression is a major obstacle to successful immunotherapy. IDO levels are correlated with increased metastasis and poor patient outcome in many hematological and solid tumors. There is ample evidence that shows IDO induces resistance to ipilimumab and hinders its effectiveness against melanoma. We have recently shown that IDO induces resistance to the PARP inhibitor olaparib, ionizing radiation, and cisplatin independent of its immune-evading functions. However, our knowledge is limited about tumor cell-autonomous effects of IDO that are independent of its well known roles in regulating and suppressing anti-tumor immune responses. We therefore sought to study the underlying mechanism involved in IDO-mediated drug resistance. IFNγ was used to induce IDO in human lung adenocarcinoma A549 cells. Most cancer cells also express IDO in vivo in response to IFNγ production from immune cells. Clonal populations of A549 cells stably-transfected with anti-IDO shRNA or scrambled control shRNA were used to study IDO effects on drug sensitivity and resistance. We show, for the first time, that IDO mediates human tumor cell resistance to NAD+ inhibitor FK866, base excision repair (BER) inhibitor methoxyamine (MX), folate anti-metabolite pemetrexed, nucleoside analogue gemcitabine, and combined treatment with pemetrexed and MX, in the absence of immune cells. Concurrent knock-down of IDO and thymidylate synthase (TS), a key rate-limiting enzyme in DNA synthesis and repair, sensitizes human lung cancer cells to drugs that are commonly used in clinic, pemetrexed and 5FUdR. Based on the differential response of cancer cells to the different drugs we used in this study, we conclude that BER in IDO-expressing A549 cells plays a major role in inducing resistance to the drugs mentioned above. IDO inhibitors are under clinical trial mostly to improve the immune response towards cancer cells in patients. Our findings underlie the central role that IDO plays in not only suppressing the anti-tumor immune response but also causing resistance to common chemotherapeutics. Debulking the tumor and eradicating the immune-suppressive environment surrounding the tumor by pretreating patients with chemotherapy and radiation before immunotherapy could increase the chance of success for the latter. However, IDO could reduce the effectiveness of the treatment and therefore targeting IDO should be considered in studies that combine conventional chemotherapy with immunotherapy.
Citation Format: Saman Maleki Vareki, Chen Di, Christine Di Cresce, Peter J. Ferguson, Mark Vincent, Weiping Min, Xiufen Zheng, James Koropatnick. The immunoregulatory enzyme IDO induces resistance to common chemotherapy drugs via base excision repair pathway. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A134.
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