Format

Send to

Choose Destination
Blood. 2015 Sep 24;126(13):1555-64. doi: 10.1182/blood-2015-01-624585. Epub 2015 Jul 20.

Direct and immune-mediated cytotoxicity of interleukin-21 contributes to antitumor effects in mantle cell lymphoma.

Author information

1
Department of Molecular and Cellular Pharmacology and Department of Medicine, Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, Miami, FL;
2
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;
3
Department of Medicine, Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, Miami, FL;
4
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; and.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA.

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.

PMID:
26194763
PMCID:
PMC4582332
DOI:
10.1182/blood-2015-01-624585
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center