Fc effector function contributes to the activity of human anti-CTLA-4 antibodies
journal contributionposted on 25.06.2020, 15:17 authored by Frederick Arce Vargas, Andrew JS Furness, Kevin Litchfield, Kroopa Joshi, Rachel Rosenthal, Ehsan Ghorani, Isabelle Solomon, Marta H Lesko, Nora Ruef, Claire Roddie, Jake Y Henry, Lavinia Spain, Assma Ben Aissa, Andrew Georgiou, Yien Ning Sophia Wong, Myles Smith, Dirk Strauss, Andrew Hayes, David Nicol, Tim O'Brien, Linda Mårtensson, Anne Ljungars, Ingrid Teige, Björn Frendéus, TRACERx Melanoma, TRACERx Renal, TRACERx Lung Consortia, Martin Pule, Teresa Marafioti, Martin Gore, James Larkin, Samra Turajlic, Charles Swanton, Karl S Peggs, Sergio A Quezada
With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches.
CTLA-4Fc-gamma receptorsIgG subclassantibody-dependent cell-mediated cytotoxicityimmune checkpointsimmune regulatory antibodiesipilimumabregulatory T cell depletiontremelimumabtumor immunotherapyAnimalsAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntineoplastic Agents, ImmunologicalCTLA-4 AntigenCell Line, TumorFemaleHumansIpilimumabMelanomaMicePolymorphism, Single NucleotideReceptors, IgGT-Lymphocytes, RegulatoryTreatment OutcomeXenograft Model Antitumor AssaysTRACERx MelanomaTRACERx RenalTRACERx Lung consortiaSwanton FC001169Turajlic FC001988Oncology & Carcinogenesis1112 Oncology and Carcinogenesis1109 Neurosciences