Depletion of tumor-infiltrating regulatory T cells with anti-CD25 requires Fc-optimization and synergizes with PD-1 blockade to eradicate established tumors

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Depletion of tumor-infiltrating regulatory T cells with anti-CD25 requires Fc-optimization and synergizes with PD-1 blockade to eradicate established tumors

Frederick Arce Vargas1, Andrew J. S. Furness1, 2, Isabelle Solomon1, Kroopa Joshi1, 2, Marta H. Lesko1, Leila Mekkaoui3, Andrew Georgiou1, Rony Dahan4, TRACERx Consortium, James Larkin2, Samra Turajlic2, Martin Gore2, Jeffrey V. Ravetch4, Teresa Marafioti5, Martin Pule3, Charles Swanton6, Karl S. Peggs1, Sergio A. Quezada1
1Cancer Immunology Unit, University College London (UCL) Cancer Institute, London, U.K.;
2The Royal Marsden NHS Foundation Trust, London, U.K.; 3Research Department of Hematology, UCL Cancer Institute, London, U.K.; 4Leonard Wagner Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, U.S.A.; 5Department of Cellular Pathology, University College London Hospital, London, U.K.; 6Translational Cancer Therapeutics Laboratory, UCL Cancer Institute, London, U.K.

Immune suppression by regulatory T cells (Treg) contributes to the establishment and progression of tumors and is considered a major obstacle for the clinical application of cancer immunotherapy. Therefore, interference with Treg is regarded as a potential therapeutic tool in cancer. CD25 has been extensively evaluated as target for Treg depletion due to its constitutive expression on this cell sub-population. However, the therapeutic activity of anti-CD25 antibodies has been limited for reasons that are not well understood. Concomitant depletion of activated CD4+ and CD8+ effector T cells has been proposed as a potential mechanism.Recent work demonstrating that depletion of tumor infiltrating Treg is a key mechanistic feature of immunomodulatory antibodies such as anti-CTLA-4 has reinvigorated the search for specific targets for Treg depletion.Here, we decipher the mechanisms underpinning the lack of therapeutic activity of anti-CD25 monoclonal antibodies previously observed in mouse models of cancer. Although the traditionally used anti-CD25 antibody (clone PC61) promotes Fc-gamma receptor III (FcγR)-dependent systemic Treg depletion in mice, its higher affinity for inhibitory FcγR-IIb upregulated on tumor-associated myeloid cells prevents depletion of tumor infiltrating Treg. Anti-CD25 (PC61) engineered to favor binding to activatory over inhibitory FcγRs within the tumor promoted efficient depletion of infiltrating Treg in established tumors, correlating with partial tumor control. Combination of Fc-optimized anti-CD25 synergized with PD-1/PDL-1 blockade promoting eradication of established tumors in several mouse models of cancer.Finally, we validated CD25 as a target preferentially expressed on Treg over Teff cells infiltrating human cancers including melanoma, renal and lung adenocarcinoma. Our data offers a novel mechanistic insight as to the relevance of intra-tumoral over systemic Treg depletion; it validates CD25 as a key target for therapeutic depletion of tumor infiltrating Treg in mice and humans and a potential substrate for novel combinations in immune-oncology, starting with PD-1/PDL-1 blockade.


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