title: Direct and immune-mediated cytotoxicity of interleukin-21 contributes to antitumor effects in mantle cell lymphoma.
abstract: Mantle cell lymphoma (MCL) is a distinct subtype of non-Hodgkin lymphoma characterized by overexpression of cyclin D1 in 95% of patients. MCL patients experience frequent relapses resulting in median survival of 3 to 5 years, requiring more efficient therapeutic regimens. Interleukin (IL)-21, a member of the IL-2 cytokine family, possesses potent antitumor activity against a variety of cancers not expressing the IL-21 receptor (IL-21R) through immune activation. Previously, we established that IL-21 exerts direct cytotoxicity on IL-21R-expressing diffuse large B-cell lymphoma cells. Herein, we demonstrate that IL-21 possesses potent cytotoxicity against MCL cell lines and primary tumors. We identify that IL-21-induced direct cytotoxicity is mediated through signal transducer and activator of transcription 3-dependent cMyc upregulation, resulting in activation of Bax and inhibition of Bcl-2 and Bcl-XL. IL-21-mediated cMyc upregulation is only observed in IL-21-sensitive cells. Further, we demonstrate that IL-21 leads to natural killer (NK)-cell-dependent lysis of MCL cell lines that were resistant to direct cytotoxicity. In vivo treatment with IL-21 results in complete FC-muMCL1 tumor regression in syngeneic mice via NK- and T-cell-dependent mechanisms. Together, these data indicate that IL-21 has potent antitumor activity against MCL cells via direct cytotoxic and indirect, immune-mediated effects.
authors.affiliation: Department of Molecular and Cellular Pharmacology and Department of Medicine, Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, Miami, FL;
authors.forename: Shruti
authors.initials: S
authors.lastname: Bhatt
authors.affiliation: Department of Molecular and Cellular Pharmacology and Department of Medicine, Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, Miami, FL;
authors.forename: Julie
authors.initials: J
authors.lastname: Matthews
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, Miami, FL; Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL;
authors.forename: Salma
authors.initials: S
authors.lastname: Parvin
authors.affiliation: Department of Molecular and Cellular Pharmacology and Department of Medicine, Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, Miami, FL;
authors.forename: Kristopher A
authors.initials: KA
authors.lastname: Sarosiek
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, Miami, FL; Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL;
authors.forename: Dekuang
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, Miami, FL;
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; and.
authors.forename: Elif
authors.initials: E
authors.lastname: Isik
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Letai
authors.affiliation: Department of Molecular and Cellular Pharmacology and Department of Medicine, Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, Miami, FL;
authors.forename: Izidore S
authors.initials: IS
authors.lastname: Lossos
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology* / Q000627:therapeutic use*; D007167:Immunotherapy; D007378:Interleukins / Q000276:immunology* / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology; D020522:Lymphoma, Mantle-Cell / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008810:Mice, Inbred C57BL; D016271:Proto-Oncogene Proteins c-myc / Q000276:immunology; D053655:Receptors, Interleukin-21 / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D007155:Immunologic Factors; D007378:Interleukins; D016271:Proto-Oncogene Proteins c-myc; D053655:Receptors, Interleukin-21; D050796:STAT3 Transcription Factor; D051028:bcl-2-Associated X Protein; D000098546:Interleukin-21