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Lymphoma

IL10 receptor is a novel therapeutic target in DLBCLs

Leukemia volume 29, pages 1684–1694 (2015)Cite this article

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Abstract

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.

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Acknowledgements

This work was supported by the start up fund from the Department of Medicine WCMC and a generous gift from Bob Horne and Laurie Lindenbaum. We thank Robert Bichard for editing the paper.

Author Contributions

WB designed and performed research and analyzed data; SS, JWC, AC and LT collected data and performed research; NC, FCC, YJ and HG analyzed data and performed statistical analysis; DS, WT, GB and RDG contributed with patient samples and interpreted data; RS designed research, interpreted data and wrote the manuscript.

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Authors and Affiliations

  1. Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY, USA

    W Béguelin, S Sawh, Y Jiang, J-W Choo, A Chalmers, L Tsikitas & R Shaknovich

  2. The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY, USA

    N Chambwe

  3. Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA

    N Chambwe

  4. Tri-Instituitional Training Program in Computational Biology and Medicine, Weill Cornell Medical College, New York, NY, USA

    N Chambwe

  5. Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada

    F C Chan, D W Scott & R D Gascoyne

  6. Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA

    H Geng

  7. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA

    W Tam

  8. Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA

    G Bhagat & R Shaknovich

  9. Department of Pathology, University of British Columbia, Vancouver, BC, Canada

    R D Gascoyne

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  1. W Béguelin
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Correspondence to R Shaknovich.

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Béguelin, W., Sawh, S., Chambwe, N. et al. IL10 receptor is a novel therapeutic target in DLBCLs. Leukemia 29, 1684–1694 (2015). https://doi.org/10.1038/leu.2015.57

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