Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors.
journal contributionposted on 18.12.2017, 14:49 by Frederick Arce Vargas, Andrew J. S. Furness, Isabelle Solomon, Kroopa Joshi, Leila Mekkaoui, Marta H. Lesko, Enrique Miranda Rota, Rony Dahan, Andrew Georgiou, Anna Sledzinska, Assma Ben Aissa, Dafne Franz, Mariana Werner Sunderland, Yien Ning Sophia Wong, Jake Y. Henry, Tim O'Brien, David Nicol, Ben Challacombe, Stephen A. Beers, Melanoma TRACERx Consortium, Renal TRACERx Consortium, Lung TRACERx Consortium, Samra Turajlic, Martin Gore, James Larkin, Charles Swanton, Kerry A. Chester, Martin Pule, Jeffrey V. Ravetch, Teresa Marafioti, Karl S. Peggs, Sergio A. Quezada
CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology.
S.A.Q. is a Cancer Research U.K. (CRUK) Senior Fellow (C36463/A22246) and is funded by a Cancer Research Institute Investigator Award and a CRUK Biotherapeutic Program Grant (C36463/A20764). K.S.P. receives funding from the NIHR BTRU for Stem Cells and Immunotherapies (167097), of which he is the Scientific Director. None of the animal work described was funded by NIHR. This work was undertaken at UCL Hospitals/UCL with support from the CRUK-UCL Centre (C416/A18088), CRUK’s Lung Cancer Centre of Excellence (C5759/A20465), the CRUK and Engineering and Physical Sciences Research Council at King's College London and UCL (C1519/A16463), the Cancer Immunotherapy Accelerator Award (CITA-CRUK) (C33499/A20265), CRUK’s Lung TRACERx study (led by C. Swanton) (C11496/A17786), the Sam Keen Foundation/RMH NIHR Biomedical Research Centre, Bloodwise (formerly Leukaemia and Lymphoma Research) (08022/P4664), the Department of Health, and CRUK funding schemes for National Institute for Health Research Biomedical Research Centres and Experimental Cancer Medicine Centres.
CitationImmunity, 2017, 46 (4), pp. 577-586
Author affiliation/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cancer Studies and Molecular Medicine
VersionVoR (Version of Record)
PublisherElsevier (Cell Press)
NotesSupplemental Information includes four figures, four tables, Supplemental Experimental Procedures, and consortia memberships and can be found with this article online at http://dx.doi.org/10.1016/j.immuni.2017.03.013.
CD25Fc gamma receptorsTreg depletionanti-CD25anti-PD-1inhibitory Fc receptorregulatory T cellstumor immunotherapytumor microenvironmentAnimalsAntibodies, MonoclonalCell Line, TumorFlow CytometryHumansImmunoglobulin Fc FragmentsImmunotherapyInterleukin-2 Receptor alpha SubunitK562 CellsKaplan-Meier EstimateLymphocyte DepletionMiceNeoplasmsProgrammed Cell Death 1 ReceptorProtein BindingReceptors, IgGT-Lymphocytes, Regulatory