Lenalidomide Induces Interleukin-21 Production by T Cells and Enhances IL21-Mediated Cytotoxicity in Chronic Lymphocytic Leukemia B Cells.
The immunomodulatory drug lenalidomide has demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL), despite a lack of direct cytotoxic effects in vitro The mechanism of lenalidomide efficacy in vivo is thought to occur via a combination of enhanced immune activity and an alteration of tumor cell-microenvironment interactions. We demonstrate in whole blood from patients with CLL that lenalidomide significantly depletes malignant B cells. Lenalidomide also induced production of interleukin-21 (IL21) and its mRNA in T cells from patients with CLL. In addition, lenalidomide enhanced upregulation of functional IL21 receptor (IL21R) on the cell surface and increased receptor mRNA in vitro The in vitro combination of IL21 and lenalidomide enhanced IL21-mediated cytotoxicity toward CLL cells through a variety of mechanisms. We show association of cell death with upregulation of Bid by IL21, enhanced upregulation of Bid by the combination therapy, and diminished Lck and downstream BCR signaling activation of Syk and PLCG2. Collectively, we demonstrated an immune cell-tumor cell interaction through lenalidomide-mediated induction of IL21 and IL21R, with enhanced IL21-mediated cytotoxicity, which provides justification for this combination in clinical trials for patients with CLL. Cancer Immunol Res; 4(8); 698-707. ©2016 AACR.
Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio.
Rebekah L
RL
Browning
Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio. Davidson College, Davidson, North Carolina.
William H
WH
Byrd
Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio.
Nikhil
N
Gupta
Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio.
Jeffrey
J
Jones
Center for Biostatistics, The Ohio State University, Columbus, Ohio.
Xiaokui
X
Mo
Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio.
Erin
E
Hertlein
Center for Biostatistics, The Ohio State University, Columbus, Ohio.
Lianbo
L
Yu
Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio. john.byrd@osumc.edu Raj.muthusamy@osumc.edu.
Natarajan
N
Muthusamy
Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio. john.byrd@osumc.edu Raj.muthusamy@osumc.edu.
John C
JC
Byrd
D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D020869:Gene Expression Profiling; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology; D007378:Interleukins / Q000378:metabolism* / Q000494:pharmacology; D000077269:Lenalidomide; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D053655:Receptors, Interleukin-21 / Q000378:metabolism; D000072377:Syk Kinase / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology*; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000098546:Interleukin-21
D007155:Immunologic Factors; D007378:Interleukins; D053655:Receptors, Interleukin-21; D013792:Thalidomide; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D000072377:Syk Kinase; D051966:Phospholipase C gamma; D000077269:Lenalidomide; D000098546:Interleukin-21