title: Reduced immunosuppressive properties of axitinib in comparison with other tyrosine kinase inhibitors.
abstract: The multikinase inhibitors sunitinib, sorafenib, and axitinib have an impact not only on tumor growth and angiogenesis, but also on the activity and function of immune effector cells. In this study, a comparative analysis of the growth inhibitory properties and apoptosis induction potentials of tyrosine kinase inhibitors on T cells was performed. Tyrosine kinase inhibitor treatment resulted in a dramatic decrease in T cell proliferation along with distinct impacts on the cell cycle progression. This was at least partially associated with an enhanced induction of apoptosis although triggered by distinct apoptotic mechanisms. In contrast to sunitinib and sorafenib, axitinib did not affect the mitochondrial membrane potential (Δψm) but resulted in an induction or stabilization of the induced myeloid leukemia cell differentiation protein (Mcl-1), leading to an irreversible arrest in the G2/M cell cycle phase and delayed apoptosis. Furthermore, the sorafenib-mediated suppression of immune effector cells, in particular the reduction of the CD8(+) T cell subset along with the down-regulation of key immune cell markers such as chemokine CC motif receptor 7 (CCR7), CD26, CD69, CD25, and CXCR3, was not observed in axitinib-treated immune effector cells. Therefore, axitinib rather than sorafenib seems to be suitable for implementation in complex treatment regimens of cancer patients including immunotherapy.
authors.affiliation: Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, 06112 Halle (Saale), Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Stehle
authors.affiliation: Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, 06112 Halle (Saale), Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Schulz
authors.affiliation: Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, 06112 Halle (Saale), Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Fahldieck
authors.affiliation: Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, 06112 Halle (Saale), Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Kalich
authors.affiliation: Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, 06112 Halle (Saale), Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Lichtenfels
authors.affiliation: Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, 06112 Halle (Saale), Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Riemann
authors.affiliation: Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, 06112 Halle (Saale), Germany. Electronic address: barbara.seliger@uk-halle.de.
authors.forename: Barbara
authors.initials: B
authors.lastname: Seliger
mesh_terms: D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D000077784:Axitinib; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007191:Indazoles / Q000494:pharmacology*; D019169:Jurkat Cells; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000276:immunology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D054400:Receptors, CCR7 / Q000276:immunology / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000276:immunology / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C515370:CCR7 protein, human; C515187:CXCR3 protein, human; D007093:Imidazoles; D007166:Immunosuppressive Agents; D007191:Indazoles; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D054400:Receptors, CCR7; D054367:Receptors, CXCR3; D000077784:Axitinib
keywords: Apoptosis; Axitinib; Immunology; Immunosuppression; Immunotherapy; Sorafenib; Sunitinib; T Cell; Targeted Therapy; Tyrosine Kinase Inhibitor