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

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cam.depositDate2022-05-18
cam.issuedOnline2022-04-07
dc.contributor.authorHussain, Khiyam
dc.contributor.authorLiu, Rena
dc.contributor.authorSmith, Rosanna CG
dc.contributor.authorMüller, Kri TJ
dc.contributor.authorGhorbani, Mohammadmersad
dc.contributor.authorMacari, Sofia
dc.contributor.authorCleary, Kirstie LS
dc.contributor.authorOldham, Robert J
dc.contributor.authorFoxall, Russell B
dc.contributor.authorJames, Sonya
dc.contributor.authorBooth, Steven G
dc.contributor.authorMurray, Tom
dc.contributor.authorDahal, Lekh N
dc.contributor.authorHargreaves, Chantal E
dc.contributor.authorKemp, Robert S
dc.contributor.authorLongley, Jemma
dc.contributor.authorDouglas, James
dc.contributor.authorMarkham, Hannah
dc.contributor.authorChee, Serena J
dc.contributor.authorStopforth, Richard J
dc.contributor.authorRoghanian, Ali
dc.contributor.authorCarter, Matthew J
dc.contributor.authorOttensmeier, Christian H
dc.contributor.authorFrendéus, Bjorn
dc.contributor.authorCutress, Ramsey I
dc.contributor.authorFrench, Ruth R
dc.contributor.authorGlennie, Martin J
dc.contributor.authorStrefford, Jonathan C
dc.contributor.authorThirdborough, Stephen M
dc.contributor.authorBeers, Stephen A
dc.contributor.authorCragg, Mark S
dc.contributor.orcidHussain, Khiyam [0000-0002-6705-4412]
dc.contributor.orcidCragg, Mark S [0000-0003-2077-089X]
dc.date.accessioned2022-05-26T23:30:12Z
dc.date.available2022-05-26T23:30:12Z
dc.date.issued2022-04-07
dc.date.updated2022-05-18T09:36:29Z
dc.description.abstractBACKGROUND: 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 FcγRIIbbright 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.
dc.format.mediumElectronic
dc.identifier.doi10.17863/CAM.84931
dc.identifier.eissn1756-9966
dc.identifier.issn0392-9078
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/337516
dc.publisherSpringer Science and Business Media LLC
dc.publisher.departmentDepartment of Medicine
dc.publisher.urlhttp://dx.doi.org/10.1186/s13046-022-02294-5
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCancer
dc.subjectFc gamma receptors
dc.subjectFcγRIIb
dc.subjectHypoxia
dc.subjectHypoxia inducible factors
dc.subjectMonoclonal antibody
dc.subjectMonocytes
dc.subjectResistance
dc.subjectTumor microenvironment
dc.subjectTumor-associated macrophages
dc.subjectAnimals
dc.subjectAntibodies, Monoclonal
dc.subjectHumans
dc.subjectHypoxia
dc.subjectImmunotherapy
dc.subjectLeukemia, Lymphocytic, Chronic, B-Cell
dc.subjectMacrophages
dc.subjectMice
dc.subjectReceptors, IgG
dc.subjectTumor Microenvironment
dc.titleHIF activation enhances FcγRIIb expression on mononuclear phagocytes impeding tumor targeting antibody immunotherapy.
dc.typeArticle
dcterms.dateAccepted2022-02-20
prism.issueIdentifier1
prism.publicationDate2022
prism.publicationNameJ Exp Clin Cancer Res
prism.startingPage131
prism.volume41
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
pubs.licence-identifierapollo-deposit-licence-2-1
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1186/s13046-022-02294-5
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