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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 (Fc\u03b3R) and impaired by the single inhibitory Fc\u03b3R, Fc\u03b3RIIb.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>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 <jats:italic>FCGR2B<\/jats:italic> gene transcription.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We report that TAMs are Fc\u03b3RIIb<jats:sup>bright<\/jats:sup> relative to healthy tissue counterparts and under hypoxic conditions<jats:italic>,<\/jats:italic> mononuclear phagocytes markedly upregulate Fc\u03b3RIIb. This enhanced Fc\u03b3RIIb 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 Fc\u03b3RIIb<jats:sup>+<jats:italic>\/<\/jats:italic>+<\/jats:sup> transgenic mice. Furthermore, post-HIF activation, mAb mediated blockade of Fc\u03b3RIIb can partially restore phagocytic function in human monocytes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>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 Fc\u03b3RIIb expression or its blockade as a promising strategy to enhance approved and novel mAb immunotherapies.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13046-022-02294-5","type":"journal-article","created":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T05:02:51Z","timestamp":1649307771000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["HIF activation enhances Fc\u03b3RIIb expression on mononuclear phagocytes impeding tumor targeting antibody immunotherapy"],"prefix":"10.1186","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6705-4412","authenticated-orcid":false,"given":"Khiyam","family":"Hussain","sequence":"first","affiliation":[]},{"given":"Rena","family":"Liu","sequence":"additional","affiliation":[]},{"given":"Rosanna C. 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The use of leukocyte cones for this work was approved by the University of Southampton Faculty of Medicine Ethics Committee and the East of Scotland Research Ethics Service, Tayside, UK, Research ethical committee (REC) reference number: 16\/ES\/0048. Clinical samples from 6 anonymized mesothelioma patients (REC reference number: 13\/SW\/0128) and Donor matched Renal cell carcinoma (RCC) and non-cancerous healthy kidney tissue samples were obtained from resected kidneys from 5 RCC patients (REC reference number: 17\/WA\/0241). Lymphocele samples were sourced from 3 anonymized breast cancer patents (REC reference number: 10\/H0504\/73, for breast cancer patient samples). Peripheral blood samples were taken from Chronic Lymphoblastic Leukemia (CLL) patients and anonymized before experimental use (REC reference number: 10\/H0504\/187). These aforementioned clinical samples were released from the Human Tissue Authority Licensed University of Southampton, Cancer Sciences Tissue Bank, as approved by the Southampton and South West Hampshire Research Ethics Committee (REC reference: 280\/99). All informed consent for the use of human material was provided in accordance with the Declaration of Helsinki.Mice were used in these studies as the least sentient species with an immune system comparable to humans. Following approval by local ethical committees, reporting to the Home Office Animal Welfare Ethical Review Board (AWERB) at the University of Southampton, in vivo experiments were conducted under UK Home Office Project licenses P81E129B7 and P4D9C89EA.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"A.R. receives funding from BioInvent International. Research by R.I.C is supported by use of equipment to measure body composition provided by SECA through a model industry collaborative agreement (mICA) with University Hospital Southampton. M.J.G previously acted as a consultant to a number of biotech companies and receives institutional payments and royalties from antibody patents and licenses. J.C.S has received funding from Roche. S.A.B acts as a consultant for a number of biotech companies and has received institutional support for grants and patents from BioInvent. M.S.C. acts as a consultant for a number of biotech companies, being retained as a consultant for BioInvent International and has received research funding from BioInvent, GSK, UCB, iTeos, and Roche.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"131"}}