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

PLoS One. 2015 May 8;10(5):e0126159. doi: 10.1371/journal.pone.0126159. eCollection 2015.

Abstract

Background: 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.

Results: 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.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autocrine Communication
  • Cell Line, Tumor
  • Cytokines / metabolism*
  • Down-Regulation
  • Drug Resistance, Neoplasm
  • Female
  • HT29 Cells
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Janus Kinase 1 / metabolism*
  • K562 Cells
  • Kynurenine / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Chaperones / metabolism
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Protein Inhibitors of Activated STAT / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • STAT1 Transcription Factor / antagonists & inhibitors
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism*
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism

Substances

  • Cytokines
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Molecular Chaperones
  • PIAS3 protein, human
  • Protein Inhibitors of Activated STAT
  • RNA, Small Interfering
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Kynurenine
  • JAK1 protein, human
  • Janus Kinase 1

Grants and funding

This work was supported by grants from the Italian Association for Cancer Research (AIRC; grant MFAG 11475; www.airc.it), the Italian Ministry of University and Research (“Future in Research program” FIRB 2012, grant RBFR12SOQ1; www.istruzione.it). JK is fellow of the Italian Foundation for Cancer Research (FIRC; www.fondazionefirc.it). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.