HIF activation enhances FcγRIIb expression on mononuclear phagocytes impeding tumor targeting antibody immunotherapy.

Autor: Hussain K; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., Liu R; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., Smith RCG; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., Müller KTJ; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., Ghorbani M; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK.; Cancer Genomics Group, Southampton Experimental Cancer Medicine Centre, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK., Macari S; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., Cleary KLS; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., Oldham RJ; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., Foxall RB; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., James S; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., Booth SG; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., Murray T; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., Dahal LN; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., Hargreaves CE; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK.; Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK., Kemp RS; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., Longley J; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., Douglas J; University Hospital Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, Hampshire, UK., Markham H; University Hospital Southampton, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, Hampshire, UK., Chee SJ; CRUK Southampton Centre, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., Stopforth RJ; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., Roghanian A; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., Carter MJ; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., Ottensmeier CH; CRUK Southampton Centre, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., Frendéus B; Preclinical Research, BioInvent International AB, Sölvegatan 41, 22370, Lund, Sweden., Cutress RI; CRUK Southampton Centre, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., French RR; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., Glennie MJ; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., Strefford JC; Cancer Genomics Group, Southampton Experimental Cancer Medicine Centre, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK., Thirdborough SM; CRUK Southampton Centre, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK., Beers SA; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK. sab@soton.ac.uk., Cragg MS; Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton, SO16 6YD, UK. msc@soton.ac.uk.
Jazyk: angličtina
Zdroj: Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2022 Apr 07; Vol. 41 (1), pp. 131. Date of Electronic Publication: 2022 Apr 07.
DOI: 10.1186/s13046-022-02294-5
Abstrakt: Background: Hypoxia is a hallmark of the tumor microenvironment (TME) and in addition to altering metabolism in cancer cells, it transforms tumor-associated stromal cells. Within the tumor stromal cell compartment, tumor-associated macrophages (TAMs) provide potent pro-tumoral support. However, TAMs can also be harnessed to destroy tumor cells by monoclonal antibody (mAb) immunotherapy, through antibody dependent cellular phagocytosis (ADCP). This is mediated via antibody-binding activating Fc gamma receptors (FcγR) and impaired by the single inhibitory FcγR, FcγRIIb.
Methods: We applied a multi-OMIC approach coupled with in vitro functional assays and murine tumor models to assess the effects of hypoxia inducible factor (HIF) activation on mAb mediated depletion of human and murine cancer cells. For mechanistic assessments, siRNA-mediated gene silencing, Western blotting and chromatin immune precipitation were utilized to assess the impact of identified regulators on FCGR2B gene transcription.
Results: We report that TAMs are FcγRIIb bright relative to healthy tissue counterparts and under hypoxic conditions, mononuclear phagocytes markedly upregulate FcγRIIb. This enhanced FcγRIIb expression is transcriptionally driven through HIFs and Activator protein 1 (AP-1). Importantly, this phenotype reduces the ability of macrophages to eliminate anti-CD20 monoclonal antibody (mAb) opsonized human chronic lymphocytic leukemia cells in vitro and EL4 lymphoma cells in vivo in human FcγRIIb +/+ transgenic mice. Furthermore, post-HIF activation, mAb mediated blockade of FcγRIIb can partially restore phagocytic function in human monocytes.
Conclusion: Our findings provide a detailed molecular and cellular basis for hypoxia driven resistance to antitumor mAb immunotherapy, unveiling a hitherto unexplored aspect of the TME. These findings provide a mechanistic rationale for the modulation of FcγRIIb expression or its blockade as a promising strategy to enhance approved and novel mAb immunotherapies.
(© 2022. The Author(s).)
Databáze: MEDLINE
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