Fc-optimized anti-CD25 depletes tumor-infiltrating regulatory T cells and synergizes with PD-1 blockade to eradicate established tumorsMore about Open Access at the Crick
Authors listFrederick Arce Vargas Andrew JS 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
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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.
Issue number 4