Arce Vargas et al. used an established mouse model expressing human (h)FcγRs to demonstrate that anti-CTLA-4 mAbs bind to highly expressed CTLA-4 on intratumoral Tregs, making them preferential targets for ADCC-mediated depletion via interactions between the Fc regions on hIgG1 or hIgG2 anti-CTLA-4 mAbs and the hFcγRs on the host innate immune cells. Treg depletion increased the CD8+ T cell/Treg ratio and resulted in enhanced antitumor immunity in inflamed tumors. High mutational burden and affinity-enhancing polymorphisms in the CD16 FcγR enhanced response rates.

With the use of a mouse model expressing human Fc-gamma receptors (FcgammaRs), 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 FcgammaR 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 FcgammaR binding, whereas poorly infiltrated tumors will likely require combination approaches.

Author Info: (1) Cancer Immunology Unit, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK

Author Info: (1) Cancer Immunology Unit, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (2) Cancer Immunology Unit, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK; The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (3) Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London NW1 1AT, UK. (4) Cancer Immunology Unit, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK; The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (5) Bill Lyons Informatics Centre, UCL Cancer Institute, London WC1E 6DD, UK; Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6DD, UK. (6) Cancer Immunology Unit, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (7) Cancer Immunology Unit, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (8) Cancer Immunology Unit, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (9) Cancer Immunology Unit, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (10) Cancer Immunology Unit, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (11) Cancer Immunology Unit, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (12) The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (13) Cancer Immunology Unit, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (14) Cancer Immunology Unit, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (15) Cancer Immunology Unit, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (16) The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (17) The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (18) The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (19) The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (20) Guy's and St Thomas' NHS Foundation Trust, London SE1 9RT, UK. (21) BioInvent International AB, 223 70 Lund, Sweden. (22) BioInvent International AB, 223 70 Lund, Sweden. (23) BioInvent International AB, 223 70 Lund, Sweden. (24) BioInvent International AB, 223 70 Lund, Sweden. (25) Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. (26) Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK. (27) The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (28) The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK. (29) The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK; Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London NW1 1AT, UK. (30) Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London NW1 1AT, UK; Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6DD, UK; Translational Cancer Therapeutics Laboratory, UCL Cancer Institute, London WC1E 6DD, UK. (31) Cancer Immunology Unit, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. Electronic address: k.peggs@ucl.ac.uk. (32) Cancer Immunology Unit, University College London (UCL) Cancer Institute, London WC1E 6DD, UK; Research Department of Haematology, UCL Cancer Institute, London WC1E 6DD, UK. Electronic address: s.quezada@ucl.ac.uk.

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