PMID- 35017153 OWN - NLM STAT- MEDLINE DCOM- 20220316 LR - 20240210 IS - 2051-1426 (Electronic) IS - 2051-1426 (Linking) VI - 10 IP - 1 DP - 2022 Jan TI - Fc-null anti-PD-1 monoclonal antibodies deliver optimal checkpoint blockade in diverse immune environments. LID - 10.1136/jitc-2021-003735 [doi] LID - e003735 AB - BACKGROUND: 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 Fcgamma receptors (FcgammaRs) 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 FcgammaRs 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 FcgammaR-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 FcgammaRs, 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:FcgammaR 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 FcgammaR-mediated resistance in vivo and allow maximal T-cell stimulation independent of the immunological environment. CI - (c) Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. FAU - Moreno-Vicente, Julia AU - Moreno-Vicente J AUID- ORCID: 0000-0002-1740-9350 AD - Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK. AD - Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK. FAU - Willoughby, Jane E AU - Willoughby JE AUID- ORCID: 0000-0002-6326-4519 AD - Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK. FAU - Taylor, Martin C AU - Taylor MC AD - Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK. FAU - Booth, Steven G AU - Booth SG AD - Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK. FAU - English, Vikki L AU - English VL AD - Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK. FAU - Williams, Emily L AU - Williams EL AD - Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK. FAU - Penfold, Christine A AU - Penfold CA AD - Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK. FAU - Mockridge, C Ian AU - Mockridge CI AD - Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK. FAU - Inzhelevskaya, Tatyana AU - Inzhelevskaya T AD - Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK. FAU - Kim, Jinny AU - Kim J AD - Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK. FAU - Chan, H T Claude AU - Chan HTC AD - Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK. FAU - Cragg, Mark S AU - Cragg MS AD - Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK. FAU - Gray, Juliet C AU - Gray JC AD - Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK. FAU - Beers, Stephen A AU - Beers SA AD - Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, University of Southampton, Southampton, UK s.a.beers@soton.ac.uk. LA - eng GR - 24721/CRUK_/Cancer Research UK/United Kingdom GR - A25139/CRUK_/Cancer Research UK/United Kingdom GR - 20537/CRUK_/Cancer Research UK/United Kingdom GR - A24721/CRUK_/Cancer Research UK/United Kingdom GR - A20537/CRUK_/Cancer Research UK/United Kingdom GR - A29286/CRUK_/Cancer Research UK/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - J Immunother Cancer JT - Journal for immunotherapy of cancer JID - 101620585 RN - 0 (Antibodies, Monoclonal) RN - 0 (Immune Checkpoint Inhibitors) RN - 0 (Programmed Cell Death 1 Receptor) SB - IM MH - Animals MH - Antibodies, Monoclonal/pharmacology/*therapeutic use MH - Disease Models, Animal MH - Humans MH - Immune Checkpoint Inhibitors/pharmacology/*therapeutic use MH - Immunotherapy/*methods MH - Mice MH - Neoplasms/*drug therapy MH - Programmed Cell Death 1 Receptor/*immunology MH - Tumor Microenvironment PMC - PMC8753441 OTO - NOTNLM OT - antibodies OT - immunotherapy OT - neoplasm OT - programmed cell death 1 receptor COIS- Competing interests: MC acts as a consultant to BioInvent and has received institutional support from BioInvent for grants and patents. JCG and SAB have received institutional support from BioInvent for grants. EDAT- 2022/01/13 06:00 MHDA- 2022/03/17 06:00 PMCR- 2022/01/11 CRDT- 2022/01/12 06:10 PHST- 2021/12/08 00:00 [accepted] PHST- 2022/01/12 06:10 [entrez] PHST- 2022/01/13 06:00 [pubmed] PHST- 2022/03/17 06:00 [medline] PHST- 2022/01/11 00:00 [pmc-release] AID - jitc-2021-003735 [pii] AID - 10.1136/jitc-2021-003735 [doi] PST - ppublish SO - J Immunother Cancer. 2022 Jan;10(1):e003735. doi: 10.1136/jitc-2021-003735.