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

Burgess, M., Mapp, S., Mazzieri, R., Cheung, C., Cahmbers, L., Mattarollo, S., Mollee, P., Gill, D. and Saunders, N. A. (2016) Increased FcγRIIB dominance contributes to the emergence of resistance to therapeutic antibodies in chronic lymphocytic leukaemia patients. Oncogene, 36 17: 2366-2376. doi:10.1038/onc.2016.387


Author Burgess, M.
Mapp, S.
Mazzieri, R.
Cheung, C.
Cahmbers, L.
Mattarollo, S.
Mollee, P.
Gill, D.
Saunders, N. A.
Title Increased FcγRIIB dominance contributes to the emergence of resistance to therapeutic antibodies in chronic lymphocytic leukaemia patients
Journal name Oncogene   Check publisher's open access policy
ISSN 0950-9232
1476-5594
Publication date 2016-10-17
Sub-type Article (original research)
DOI 10.1038/onc.2016.387
Open Access Status Not yet assessed
Volume 36
Issue 17
Start page 2366
End page 2376
Total pages 11
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2017
Language eng
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.
Keyword Therapeutic antibodies
Chronic lymphocytic leukaemia
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Medicine Publications
UQ Diamantina Institute Publications
 
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Created: Thu, 06 Apr 2017, 12:03:40 EST by Kylie Hengst on behalf of Research Strategy and Support (Medicine)