IL10 receptor is a novel therapeutic target in DLBCLs.
Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease with marked genomic instability and variable response to conventional R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy. More clinically aggressive cases of DLBCLs have high level of circulating interleukin 10 (IL10) cytokine and evidence of activated intracellular STAT3 (signal transducer and activator of transcription 3) signaling. We investigated the role of IL10 and its surface receptor in supporting the neoplastic phenotype of DLBCLs. We determined that IL10RA gene is amplified in 21% and IL10RB gene in 10% of primary DLBCLs. Gene expression of IL10, IL10RA and IL10RB was markedly elevated in DLBCLs. We hypothesized that DLBCLs depend for their proliferation and survival on IL10-STAT3 signaling and that blocking the IL10 receptor (IL10R) would induce cell death. We used anti-IL10R blocking antibody, which resulted in a dose-dependent cell death in all tested activated B-cell-like subtype of DLBCL cell lines and primary DLBCLs. Response of germinal center B-cell-like subtype of DLBCL cell lines to anti-IL10R antibody varied from sensitive to resistant. Cells underwent cell cycle arrest, followed by induction of apoptosis. Cell death depended on inhibition of STAT3 and, to a lesser extent, STAT1 signaling. Anti-IL10R treatment resulted in interruption of IL10-IL10R autostimulatory loop. We thus propose that IL10R is a novel therapeutic target in DLBCLs.
Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY, USA.
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Béguelin
Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY, USA.
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Sawh
1] The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY, USA [2] Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA [3] Tri-Instituitional Training Program in Computational Biology and Medicine, Weill Cornell Medical College, New York, NY, USA.
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Chambwe
Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada.
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Chan
Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY, USA.
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Jiang
Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY, USA.
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Choo
Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada.
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Scott
Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY, USA.
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Chalmers
Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.
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Geng
Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY, USA.
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Tsikitas
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
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Tam
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
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Bhagat
1] Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada [2] Department of Pathology, University of British Columbia, Vancouver, BC, Canada.
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Gascoyne
1] Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY, USA [2] Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
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Shaknovich
D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007124:Immunoenzyme Techniques; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D053701:Receptors, Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D053701:Receptors, Interleukin-10; D016753:Interleukin-10