title: Ex vivo evaluation of the effect of regulatory T cells on the anti-tumor activity of bortezomib in multiple myeloma.
abstract: Multiple myeloma (MM) is a hematologic cancer characterized by malignant proliferation of plasma cells and their precursors. Immunosuppressive CD4+CD25+Foxp3+ regulatory T (Treg) cells are increased in the peripheral blood of patients with MM. On the basis of this finding, we sought to evaluate the ex vivo effect of CD4+CD25+Foxp3+ Treg cells on the anti-tumor effect of the proteosome inhibitor bortezomib on MM cells. We collected peripheral blood and bone marrow aspiration samples from 20 patients with newly diagnosed MM and isolated CD4+CD25+Foxp3+ Treg cells from peripheral blood mononuclear cells. The bone marrow mononuclear cells were cultivated in RPMI at 37°C and 5% CO2 for 72 hours. The LD50 doses of bortezomib, isolated Treg cells, and their combination were added. After 24 hours, the viability of CD138+ myeloma cells was evaluated by WST-1. We compared the anti-tumor effect of bortezomib alone and in combination with Treg expansion and statistically analyzed the measured differences with respect to the clinical parameters of the patients. Treg cells had varied effects on bortezomib, increasing, decreasing, or not changing its anti-tumor effect. The increased in vitro anti-tumor effect of bortezomib after Treg cell expansion was correlated in patients who did not develop bortezomib resistance in vivo (p = 0.022). These patients with in vivo non-bortezomib-resistant MM also responded to Treg expansion with decreased cell viability (p = 0.024). Our data indicate that the ex vivo expansion of Treg cells increased the cytotoxic effect of bortezomib in clinically sensitive cases.
authors.affiliation: Department of Basic Oncology, Institute of Oncology, Dokuz Eylul University, Izmir, Turkey. Electronic address: pinarercetin@gmail.com.
authors.forename: Ayse Pinar
authors.initials: AP
authors.lastname: Ercetin
authors.affiliation: Department of Clinical Oncology, Institute of Oncology, Dokuz Eylul University, Izmir, Turkey.
authors.forename: Mehmet Ali
authors.initials: MA
authors.lastname: Ozcan
authors.affiliation: Department of Basic Oncology, Institute of Oncology, Dokuz Eylul University, Izmir, Turkey.
authors.forename: Safiye
authors.initials: S
authors.lastname: Aktas
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
authors.forename: Faize
authors.initials: F
authors.lastname: Yuksel
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
authors.forename: Serife Medeni
authors.initials: SM
authors.lastname: Solmaz
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
authors.forename: Gokmen Omur
authors.initials: GO
authors.lastname: Sevindik
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Katgi
authors.affiliation: Department of Preventive Oncology, Institute of Oncology, Dokuz Eylul University, Izmir, Turkey.
authors.forename: Ozden
authors.initials: O
authors.lastname: Piskin
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey.
authors.forename: Bulent
authors.initials: B
authors.lastname: Undar
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000954:Antigens, Surface / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D000069286:Bortezomib / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D009367:Neoplasm Staging; D053668:Syndecan-1 / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D000970:Antineoplastic Agents; D015415:Biomarkers; D053668:Syndecan-1; D000069286:Bortezomib