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Increased FcγRIIB dominance contributes to the emergence of resistance to therapeutic antibodies in chronic lymphocytic leukaemia patients

Oncogene volume 36, pages 2366–2376 (2017)Cite this article

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Abstract

Resistance to therapeutic antibodies in chronic lymphocytic leukaemia (CLL) is common. In this study, we show that therapeutic antibodies against CD62L (CD62L-Ab) or CD20 (obinutuzumab) were able to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and phagocytosis (ADP) in primary cultures of CLL cells. CLL cells derived from patients with active disease requiring treatment displayed resistance to these antibodies, whereas patients with stable disease were sensitive. Using enrichment strategies and transcriptomic analyses, we show that antibody-dependent tumour cell killing was FcγR-dependent and mediated by macrophages. Moreover, we show that resistance cannot be attributed to total numbers or established subtypes of monocytes/macrophages, or the efficiency with which they bind an immune complex. Rather, ADCC/ADP resistance was due to reduced signalling activity through the activating FcγRs resulting in the transfer of dominance to the inhibitory FcγRIIb within macrophages. Most significantly, we show that resistance is an actionable event that could be reversed using inhibitors of FcγRIIb signalling in primary cultures of CLL cells that were previously insensitive to obinutuzumab or CD62L-Ab.

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Acknowledgements

We gratefully acknowledge the patients who donated samples for this study. We also gratefully acknowledge the constructive comments of Professor Maher Gandhi before submission. NS is supported by grants from the Australian NHMRC (#APP1049182) and the Cancer Council Queensland (#APP1025479). NS is supported by a Senior Research Fellowship awarded by the Cancer Council Queensland.

Author contributions

MB designed and performed the research, analysed the data and wrote the paper; SM designed the research, analysed the data, provided the patient samples and wrote the paper. RM and SRM designed the research and edited the manuscript; CC and LC designed and performed the research; PM provided the patient samples, analysed the clinical data and edited the manuscript; DG supervised the study, designed the research, provided the patient samples and edited the manuscript; NAS supervised the study, designed the research, analysed the data and wrote the manuscript.

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Author notes

  1. M Burgess and S Mapp: These authors contributed equally to this work.

Authors and Affiliations

  1. The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia

    M Burgess, R Mazzieri, S R Mattarollo, D Gill & N A Saunders

  2. Department of Haematology, Cancer Services, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia

    M Burgess, S Mapp, C Cheung, L Chambers, P Mollee & D Gill

  3. University of Queensland School of Medicine, Translational Research Institute, Woolloongabba, Queensland, Australia

    P Mollee

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  1. M Burgess
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Correspondence to D Gill or N A Saunders.

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Burgess, M., Mapp, S., Mazzieri, R. et al. Increased FcγRIIB dominance contributes to the emergence of resistance to therapeutic antibodies in chronic lymphocytic leukaemia patients. Oncogene 36, 2366–2376 (2017). https://doi.org/10.1038/onc.2016.387

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