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Chronic lymphocytic leukemia

Ibrutinib modulates the immunosuppressive CLL microenvironment through STAT3-mediated suppression of regulatory B-cell function and inhibition of the PD-1/PD-L1 pathway

Leukemia volume 32, pages 960–970 (2018)Cite this article

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Abstract

Ibrutinib, a covalent inhibitor of Bruton Tyrosine Kinase (BTK), is approved for treatment of patients with relapsed/refractory or treatment-naïve chronic lymphocytic leukemia (CLL). Besides directly inhibiting BTK, ibrutinib possesses immunomodulatory properties through targeting multiple signaling pathways. Understanding how this ancillary property of ibrutinib modifies the CLL microenvironment is crucial for further exploration of immune responses in this disease and devising future combination therapies. Here, we investigated the mechanisms underlying the immunomodulatory properties of ibrutinib. In peripheral blood samples collected prospectively from CLL patients treated with ibrutinib monotherapy, we observed selective and durable downregulation of PD-L1 on CLL cells by 3 months post-treatment. Further analysis showed that this effect was mediated through inhibition of the constitutively active signal transducer and activator of transcription 3 (STAT3) in CLL cells. Similar downregulation of PD-1 was observed in CD4+ and CD8+ T cells. We also demonstrated reduced interleukin (IL)-10 production by CLL cells in patients receiving ibrutinib, which was also linked to suppression of STAT3 phosphorylation. Taken together, these findings provide a mechanistic basis for immunomodulation by ibrutinib through inhibition of the STAT3 pathway, critical in inducing and sustaining tumor immune tolerance. The data also merit testing of combination treatments combining ibrutinib with agents capable of augmenting its immunomodulatory effects.

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Acknowledgements

This work was funded in part by CLL Moonshot, the CLL Global Foundation and by a research grant from Pharmacyclics. This work was supported in part by the National Institutes of Health (PO1-CA81534) of the CLL Research Consortium. The flow studies were performed in the Flow Cytometry & Cellular Imaging Facility, which is supported in part by the National Institutes of Health through MD Anderson's Cancer Center Support Grant CA016672.

Author contribution

KK and HS performed experiments, designed, interpreted, analyzed and wrote the manuscript. DH and EK assisted with experiments and commented on the manuscript. PAT analyzed data and wrote the manuscript. JAB, ZE, MK, MM, NI, AA, WW, NJ, EL and EJS provided advice on experiments and commented on the manuscript. KR designed and directed the study and wrote the manuscript.

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  1. K Kondo and H Shaim: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    K Kondo, H Shaim, M Daher, R Basar, M Muftuoglu, N Imahashi, A Alsuliman, C Sobieski, E Gokdemir, E Liu, E J Shpall & K Rezvani

  2. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    P A Thompson, J A Burger, M Keating, Z Estrov, D Harris, E Kim, A Ferrajoli, W Wierda & N Jain

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  1. K Kondo
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Kondo, K., Shaim, H., Thompson, P. et al. Ibrutinib modulates the immunosuppressive CLL microenvironment through STAT3-mediated suppression of regulatory B-cell function and inhibition of the PD-1/PD-L1 pathway. Leukemia 32, 960–970 (2018). https://doi.org/10.1038/leu.2017.304

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