title: An Autocrine Cytokine/JAK/STAT-Signaling Induces Kynurenine Synthesis in Multidrug Resistant Human Cancer Cells.
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.
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy.
authors.forename: Ivana
authors.initials: I
authors.lastname: Campia
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Buondonno
authors.affiliation: Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy; Division of Hematology, University of Torino, Torino, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Castella
authors.affiliation: Department of Drug Science and Technology, University of Torino, Torino, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Rolando
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy.
authors.forename: Joanna
authors.initials: J
authors.lastname: Kopecka
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Gazzano
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy; Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Ghigo
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy; Center for Experimental Research and Medical Studies (CeRMS), University of Torino, Torino, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Riganti
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D019073:HT29 Cells; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D053613:Janus Kinase 1 / Q000378:metabolism*; D020014:K562 Cells; D007737:Kynurenine / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018832:Molecular Chaperones / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018832:Molecular Chaperones; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D007737:Kynurenine; C507904:JAK1 protein, human; D053613:Janus Kinase 1