B-CLL cells acquire APC- and CTL-like phenotypic characteristics after stimulation with CpG ODN and IL-21.
CpG oligodeoxynucleotides (CpG) and IL-21 are two promising agents for the treatment of B-cell chronic lymphocytic leukemia (B-CLL). Recently, we reported that the combination of CpG and IL-21 (CpG/IL-21) can induce granzyme B (GrB)-dependent apoptosis in B-CLL cells. Here, we demonstrate that treatment of B-CLL cells with CpG and IL-21 results in the development of antigen-presenting cell (APC)-like cells with cytotoxic features. These properties eventually give rise to B-CLL cell apoptosis, independently of their cytogenetic phenotype, whereas normal B-cell survival is not negatively affected by CpG/IL-21. APC- and CTL-typical molecules found to be up-regulated in CpG/IL-21-stimulated B-CLL cells include GrB, perforin, T-bet, monokine-induced by IFN-γ and IFN-γ-inducible protein 10 (IP-10), as well as molecules important for cell adhesion, antigen cross-presentation and costimulation. Also induced are molecules involved in GrB induction, trafficking and processing, whereas the GrB inhibitor Serpin B9 [formerly proteinase inhibitor-9 (PI-9)] is down-modulated by CpG/IL-21. In conclusion, CpG/IL-21-stimulated B-CLL cells acquire features that are reminiscent of killer dendritic cells, and which result in enhanced immunogenicity, cytotoxicity and apoptosis. Our results provide novel insights into the aberrant immune state of B-CLL cells and may establish a basis for the development of an innovative cellular vaccination approach in B-CLL.
Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3002, Australia.
Magdalena
M
Hagn
Department of Internal Medicine, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA.
Sue E
SE
Blackwell
Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service Baden-Württemberg - Hessen and Institute of Transfusion Medicine.
Thamara
T
Beyer
Institute of Pharmacology of Natural Products and Clinical Pharmacology.
Verena
V
Ebel
Department of Pediatrics and.
Dorit
D
Fabricius
Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service Baden-Württemberg - Hessen and Institute of Transfusion Medicine.
Stefanie
S
Lindner
Department of Internal Medicine III, Ulm University, Ulm 89081, Germany.
Stefan
S
Stilgenbauer
Institute of Pharmacology of Natural Products and Clinical Pharmacology.
Thomas
T
Simmet
Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3002, Australia.
Constantine
C
Tam
Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3002, Australia.
Paul
P
Neeson
Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne 3002, Australia.
Joseph A
JA
Trapani
Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service Baden-Württemberg - Hessen and Institute of Transfusion Medicine.
Hubert
H
Schrezenmeier
Department of Internal Medicine, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA.
George J
GJ
Weiner
Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service Baden-Württemberg - Hessen and Institute of Transfusion Medicine, bernd.jahrsdoerfer@uni-ulm.de.
Bernd
B
Jahrsdörfer
D000368:Aged; D000369:Aged, 80 and over; D000938:Antigen-Presenting Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D054357:Chemokine CXCL10 / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D053804:Granzymes / Q000235:genetics / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D007378:Interleukins / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D054353:Perforin / Q000235:genetics / Q000276:immunology; D061251:Primary Cell Culture; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology; D000098815:T-bet Transcription Factor; D000098546:Interleukin-21
C408982:CPG-oligonucleotide; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D007378:Interleukins; D009838:Oligodeoxyribonucleotides; D011994:Recombinant Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D054353:Perforin; D053804:Granzymes; D000098546:Interleukin-21
cross-presentation; cytotoxic B cells; immunogenization; leukemia vaccine; toll-like receptor agonist