Abstract
BackgroundMultidrug resistant cancer cells are hard to eradicate for the inefficacy of conventional anticancer drugs. Besides escaping the cytotoxic effects of chemotherapy, they also bypass the pro-immunogenic effects induced by anticancer drugs: indeed they are not well recognized by host dendritic cells and do not elicit a durable anti-tumor immunity. It has not yet been investigated whether multidrug resistant cells have a different ability to induce immunosuppression than chemosensitive ones. We addressed this issue in human and murine chemosensitive and multidrug resistant cancer cells.ResultsWe found that the activity and expression of indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes the conversion of tryptophan into the immunosuppressive metabolite kynurenine, was higher in all the multidrug resistant cells analyzed and that IDO1 inhibition reduced the growth of drug-resistant tumors in immunocompetent animals. In chemoresistant cells the basal activity of JAK1/STAT1 and JAK1/STAT3 signaling was higher, the STAT3 inhibitor PIAS3 was down-regulated, and the autocrine production of STAT3-target and IDO1-inducers cytokines IL-6, IL-4, IL-1β, IL-13, TNF-α and CD40L, was increased. The disruption of the JAK/STAT signaling lowered the IDO1 activity and reversed the kynurenine-induced pro-immunosuppressive effects, as revealed by the restored proliferation of T-lymphocytes in STAT-silenced chemoresistant cells.ConclusionsOur work shows that multidrug resistant cells have a stronger immunosuppressive attitude than chemosensitive cells, due to the constitutive activation of the JAK/STAT/IDO1 axis, thus resulting chemo- and immune-evasive. Disrupting this axis may significantly improve the efficacy of chemo-immunotherapy protocols against resistant tumors.
Highlights
Achieving a good chemotherapy efficacy and inducing a durable anti-tumor immune response are the main challenges of chemoimmunotherapy
We found that the activity and expression of indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes the conversion of tryptophan into the immunosuppressive metabolite kynurenine, was higher in all the multidrug resistant cells analyzed and that IDO1 inhibition reduced the growth of drug-resistant tumors in immunocompetent animals
Our work shows that multidrug resistant cells have a stronger immunosuppressive attitude than chemosensitive cells, due to the constitutive activation of the JAK/STAT/IDO1 axis, resulting chemo- and immune-evasive
Summary
Achieving a good chemotherapy efficacy and inducing a durable anti-tumor immune response are the main challenges of chemoimmunotherapy. MDR can be present at the diagnosis or induced by the selective pressure of chemotherapy; it often relies on the overexpression of ATP binding cassette (ABC) transporters responsible for the anticancer drug efflux, such as P-glycoprotein (Pgp), MDR related proteins (MRPs) and breast cancer resistance protein (BCRP) Together, they efflux both classical chemotherapeutic agents (e.g. anthracyclines, taxanes, Vinca alkaloids, epipodophyllotoxins, topotecan, methotrexate) and new targeted drugs (e.g. imatinib, dasatinib, lapatinib, gefitinib, sorafenib, erlotinib), limiting their cytotoxic effects [2]. Besides escaping the cytotoxic effects of chemotherapy, they bypass the pro-immunogenic effects induced by anticancer drugs: they are not well recognized by host dendritic cells and do not elicit a durable anti-tumor immunity It has not yet been investigated whether multidrug resistant cells have a different ability to induce immunosuppression than chemosensitive ones. We addressed this issue in human and murine chemosensitive and multidrug resistant cancer cells.
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