title: AZD1480 delays tumor growth in a melanoma model while enhancing the suppressive activity of myeloid-derived suppressor cells.
abstract: AZD1480 is a potent, competitive small-molecule inhibitor of JAK1/2 kinase which inhibits STAT3 phosphorylation and tumor growth. Here we investigated the effects of AZD1480 on the function of different immune cell populations in a melanoma model. When MO4 tumor-bearing mice were treated with AZD1480 we observed a strong inhibition of tumor growth as well as a prolonged survival. Moreover, a significant decrease in the percentage of myeloid-derived suppressor cells (MDSCs) was observed after treatment with AZD1480. However, AZD1480 enhanced the suppressive capacity of murine MDSCs while at the same time impairing the proliferative as well as the IFN-γ secretion capacity of murine T cells. The addition of AZD1480 to co-cultures of human MDSCs and T cells does not affect the suppressive activity of MDSCs but it does reduce the IFN-γ secretion and the proliferative capacity of T cells. We showed that although AZD1480 has the ability to delay the tumor growth of MO4 tumor-bearing mice, this drug has detrimental effects on several aspects of the immune system. These data indicate that systemic targeting of the JAK/STAT pathway by JAK1/2 inhibition can have divergent effects on tumor growth and anti-tumor immune responses.
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Immunology-Physiology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Maenhout
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Immunology-Physiology, Vrije Universiteit Brussel, Brussels, Belgium. Department of Medical Oncology, Universiteit Ziekenhuis Brussel, Brussels, Belgium.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Du Four
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Immunology-Physiology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Corthals
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Immunology-Physiology, Vrije Universiteit Brussel, Brussels, Belgium. Department of Medical Oncology, Universiteit Ziekenhuis Brussel, Brussels, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Neyns
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Immunology-Physiology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Thielemans
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Immunology-Physiology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Joeri L
authors.initials: JL
authors.lastname: Aerts
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects* / Q000276:immunology; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011897:Random Allocation; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: C545606:AZD 1480; D011720:Pyrazoles; D011743:Pyrimidines; D053614:Janus Kinase 2