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HDAC7 is an actionable driver of therapeutic antibody resistance by macrophages from CLL patients

Oncogene volume 39, pages 5756–5767 (2020)Cite this article

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A Correction to this article was published on 22 December 2020

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Abstract

Resistance, to therapeutic antibodies used to treat chronic lymphocytic leukemia (CLL) patients is common. Monocyte-derived macrophages (MDMs) are a major effector of antitumour responses to therapeutic antibodies and we have previously reported that resistance to therapeutic antibodies, by MDMs, increases as CLL disease progresses. In this study, we examine the effect of a Class IIa-selective HDAC inhibitor (TMP195) on the phagocytic response to opsonised tumor cells or non-opsonised targets by MDMs derived from CLL patients. We report that TMP195 enhances phagocytic responses to antibody-opsonised CLL cells and E. coli within 30 min of treatment. The enhanced response is phenocopied by knockdown of the Class IIa HDAC, HDAC7, or by low concentrations of the pan-HDAC inhibitor, vorinostat. HDAC7 knockdown and inhibition induces hyperacetylation and hyperphosphorylation of Bruton’s tyrosine kinase (BTK). Moreover, BTK inhibitors abrogated the enhanced response to HDAC7 inhibition. Our data show that HDAC7 is an actionable driver of resistance to therapeutic antibodies by MDMs derived from CLL patients.

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Fig. 1: TMP195 and vorinostat enhances FcγR-dependent ADP responses to obinutuzumab and rituximab.
Fig. 2: TMP195 and vorinostat increase FcγR-independent phagocytosis.
Fig. 3: Global histone H3 hyperacetylation is not required for TMP195/vorinostat-enhanced ADP.
Fig. 4: HDAC7 knockdown enhances FcγR-dependent and FcγR-independent phagocytosis.
Fig. 5: TMP195 and vorinostat induce rapid changes in ADP and phagocytic responses in MDMs.
Fig. 6: HDAC7-dependent regulation of phagocytosis is mediated via BTK.
Fig. 7: Diagram of the proposed shared pathway controlling FcγR-dependent and FcγR-independent phagocytic responses in MDMs from CLL patients.

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Acknowledgements

The authors acknowledge the generosity of the patients who donated their time and blood for this study. This work was supported by a generous donation from Jeff and Fran Maclean and a research support package to DG from Queensland Health, Princess Alexandra Hospital.

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Authors and Affiliations

  1. University of Queensland, Woolloongabba, QLD, Australia

    M. Burgess, Y. C. E. Chen & N. A. Saunders

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

    M. Burgess, S. Mapp, P. Mollee & D. Gill

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

    S. Mapp

  4. University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, QLD, Australia

    A. Blumenthal

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Burgess, M., Chen, Y.C.E., Mapp, S. et al. HDAC7 is an actionable driver of therapeutic antibody resistance by macrophages from CLL patients. Oncogene 39, 5756–5767 (2020). https://doi.org/10.1038/s41388-020-01394-w

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