Journal Article

An Autocrine Cytokine/JAK/STAT-Signaling Induces Kynurenine Synthesis in Multidrug Resistant Human Cancer Cells

Kopecka, Joanna, Campia, Ivana, Rolando, Barbara, Buondonno, Ilaria, Ghigo, Dario, Castella, Barbara, Gazzano, Elena, Riganti, Chiara

2015

Overview

Multidrug 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. 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. 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. 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, thus resulting chemo- and immune-evasive. Disrupting this axis may significantly improve the efficacy of chemo-immunotherapy protocols against resistant tumors.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Animals / Anticancer properties / Antineoplastic drugs / Antitumor agents / Autocrine Communication / Autocrine signalling / Breast cancer / Cancer / Cancer cells / CD40L protein / Cell Line, Tumor / Cell proliferation / Chemotherapy / Cytokines / Cytokines - metabolism / Cytotoxicity / Dendritic cells / Down-Regulation / Drug resistance / Drug Resistance, Neoplasm / Drugs / Female / HT29 Cells / Humans / Immunity / Immunogenicity / Immunosuppression / Immunosuppressive agents / Immunotherapy / Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism / Interleukin 13 / Interleukin 4 / Interleukin 6 / Janus kinase / Janus Kinase 1 - metabolism / K562 Cells / Kynurenine - metabolism / Laboratories / Lung cancer / Lymphocytes / Lymphocytes T / Medical prognosis / Medical research / Mesothelioma / Metabolites / Metastasis / Mice / Mice, Inbred BALB C / Mice, Nude / Molecular Chaperones - metabolism / Multidrug resistance / Multidrug resistant organisms / Neoplasms - metabolism / Neoplasms - pathology / Oncology / Protein Inhibitors of Activated STAT - metabolism / RNA Interference / RNA, Small Interfering - metabolism / Signal Transduction / Stat1 protein / STAT1 Transcription Factor - antagonists & inhibitors / STAT1 Transcription Factor - genetics / STAT1 Transcription Factor - metabolism / Stat3 protein / STAT3 Transcription Factor - antagonists & inhibitors / STAT3 Transcription Factor - genetics / STAT3 Transcription Factor - metabolism / T-Lymphocytes - cytology / T-Lymphocytes - immunology / T-Lymphocytes - metabolism / Tryptophan / Tryptophan 2,3-dioxygenase / Tumor necrosis factor / Tumors