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

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, in...

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Bibliographic Details
Published in:Oncogene 2020-08, Vol.39 (35), p.5756-5767
Main Authors: Burgess, M., Chen, Y. C. E., Mapp, S., Blumenthal, A., Mollee, P., Gill, D., Saunders, N. A.
Format: Article
Language:English
Subjects:
631/250/251
631/67/1990/283/1895
Antibodies
Apoptosis
B cells
Biopharmaceutics
Bruton's tyrosine kinase
Cell Biology
Chronic lymphocytic leukemia
Drug Resistance, Neoplasm - drug effects
Escherichia coli
Health aspects
Histone deacetylase
Histone Deacetylases - metabolism
Human Genetics
Humans
Internal Medicine
Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy
Lymphatic leukemia
Macrophages
Macrophages - metabolism
Medical research
Medicine
Medicine & Public Health
Medicine, Experimental
Monocytes
Oncology
Phagocytes
Phosphorylation
Protein-tyrosine kinase
Tumor cells
Viral antibodies
Vorinostat
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Summary: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.
ISSN:0950-9232
1476-5594
DOI:10.1038/s41388-020-01394-w