Lenalidomide treatment promotes CD154 expression on CLL cells and enhances production of antibodies by normal B cells through a PI3-kinase-dependent pathway.
Chronic lymphocytic leukemia (CLL) involves a profound humoral immune defect and tumor-specific humoral tolerance that directly contribute to disease morbidity and mortality. CD154 gene therapy can reverse this immune defect, but attempts to do this pharmacologically have been unsuccessful. The immune-modulatory agent lenalidomide shows clinical activity in CLL, but its mechanism is poorly understood. Here, we demonstrate that lenalidomide induces expression of functional CD154 antigen on CLL cells both in vitro and in vivo. This occurs via enhanced CD154 transcription mediated by a Nuclear Factor of Activated T cells c1 (NFATc1)/Nuclear Factor-kappaB (NF-kappaB) complex and also through phosphoinositide-3 (PI3)-kinase pathway-dependent stabilization of CD154 mRNA. Importantly, CD154-positive CLL cells up-regulate BID, DR5, and p73, become sensitized to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis, and promote costimulatory activation of normal B cells to produce antibodies. In CLL patients receiving lenalidomide, similar evidence of CD154 activation is observed including BID, DR5, and p73 induction and also development of anti-ROR1 tumor-directed antibodies. Our data demonstrate that lenalidomide promotes CD154 expression on CLL cells with subsequent activation phenotype, and may therefore reverse the humoral immune defect observed in this disease. This study is registered at http://clinicaltrials.gov as NCT00466895.
Lapalombella
Rosa
R
Division of Hematology and Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA.
Andritsos
Leslie
L
Liu
Qing
Q
May
Sarah E
SE
Browning
Rebekah
R
Pham
Lan V
LV
Blum
Kristie A
KA
Blum
William
W
Ramanunni
Asha
A
Raymond
Chelsey A
CA
Smith
Lisa L
LL
Lehman
Amy
A
Mo
Xiaokui
X
Jarjoura
David
D
Chen
Ching-Shih
CS
Ford
Richard
R
Rader
Christoph
C
Muthusamy
Natarajan
N
Johnson
Amy J
AJ
Byrd
John C
JC
D000276:Adjuvants, Immunologic / Q000494:pharmacology* / Q000627:therapeutic use; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000096:biosynthesis / Q000235:genetics; D023201:CD40 Ligand / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D016130:Immunophenotyping; D000077269:Lenalidomide; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D050778:NFATC Transcription Factors / Q000502:physiology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D051023:BH3 Interacting Domain Death Agonist Protein; D023201:CD40 Ligand; D004268:DNA-Binding Proteins; D000077269:Lenalidomide; D050778:NFATC Transcription Factors; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D013792:Thalidomide; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C494814:BID protein, human; C494003:NFATC1 protein, human; C000606460:TP73 protein, human