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dc.contributor.authorMoreno-Vicente, Julia
dc.contributor.authorWilloughby, Jane E
dc.contributor.authorTaylor, Martin C
dc.contributor.authorBooth, Steven G
dc.contributor.authorEnglish, Vikki L
dc.contributor.authorWilliams, Emily L
dc.contributor.authorPenfold, Christine A
dc.contributor.authorMockridge, C Ian
dc.contributor.authorInzhelevskaya, Tatyana
dc.contributor.authorKim, Jinny
dc.contributor.authorChan, HT Claude
dc.contributor.authorCragg, Mark S
dc.contributor.authorGray, Juliet C
dc.contributor.authorBeers, Stephen A
dc.date.accessioned2022-01-28T16:34:04Z
dc.date.available2022-01-28T16:34:04Z
dc.date.issued2022-01
dc.identifier.issn2051-1426
dc.identifier.otherjitc-2021-003735
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/333138
dc.description.abstractBACKGROUND: Despite extensive clinical use, the mechanisms that lead to therapeutic resistance to anti-programmed cell-death (PD)-1 monoclonal antibodies (mAbs) remain elusive. Here, we sought to determine how interactions between the Fc region of anti-PD-1 mAbs and Fcγ receptors (FcγRs) affect therapeutic activity and how these are impacted by the immune environment. METHODS: Mouse and human anti-PD-1 mAbs with different Fc binding profiles were generated and characterized in vitro. The ability of these mAbs to elicit T-cell responses in vivo was first assessed in a vaccination setting using the model antigen ovalbumin. The antitumor activity of anti-PD-1 mAbs was investigated in the context of immune 'hot' MC38 versus 'cold' neuroblastoma tumor models, and flow cytometry performed to assess immune infiltration. RESULTS: Engagement of activating FcγRs by anti-PD-1 mAbs led to depletion of activated CD8 T cells in vitro and in vivo, abrogating therapeutic activity. Importantly, the extent of this Fc-mediated modulation was determined by the surrounding immune environment. Low FcγR-engaging mouse anti-PD-1 isotypes, which are frequently used as surrogates for human mAbs, were unable to expand ovalbumin-reactive CD8 T cells, in contrast to Fc-null mAbs. These results were recapitulated in mice expressing human FcγRs, in which clinically relevant hIgG4 anti-PD-1 led to reduced endogenous expansion of CD8 T cells compared with its engineered Fc-null counterpart. In the context of an immunologically 'hot' tumor however, both low-engaging and Fc-null mAbs induced long-term antitumor immunity in MC38-bearing mice. Finally, a similar anti-PD-1 isotype hierarchy was demonstrated in the less responsive 'cold' 9464D neuroblastoma model, where the most effective mAbs were able to delay tumor growth but could not induce long-term protection. CONCLUSIONS: Our data collectively support a critical role for Fc:FcγR interactions in inhibiting immune responses to both mouse and human anti-PD-1 mAbs, and highlight the context-dependent effect that anti-PD-1 mAb isotypes can have on T-cell responses. We propose that engineering of Fc-null anti-PD-1 mAbs would prevent FcγR-mediated resistance in vivo and allow maximal T-cell stimulation independent of the immunological environment.
dc.languageen
dc.publisherBMJ
dc.subjectBasic tumor immunology
dc.subject1506
dc.subject2434
dc.subjectimmunotherapy
dc.subjectprogrammed cell death 1 receptor
dc.subjectantibodies
dc.subjectneoplasm
dc.titleFc-null anti-PD-1 monoclonal antibodies deliver optimal checkpoint blockade in diverse immune environments.
dc.typeArticle
dc.date.updated2022-01-28T16:34:03Z
prism.issueIdentifier1
prism.publicationNameJ Immunother Cancer
prism.volume10
dc.identifier.doi10.17863/CAM.80561
dcterms.dateAccepted2021-12-08
rioxxterms.versionofrecord10.1136/jitc-2021-003735
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.licenseref.startdate2022-01-11
dc.contributor.orcidMoreno-Vicente, Julia [0000-0002-1740-9350]
dc.contributor.orcidWilloughby, Jane E [0000-0002-6326-4519]
dc.identifier.eissn2051-1426
pubs.funder-project-idCancer Research UK (A20537, A24721, A25139, A29286)
cam.issuedOnline2022-01-11
rioxxterms.freetoread.startdate2022-01-11
rioxxterms.freetoread.startdate2022-01-11


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