Article The Rockefeller University Press $30.00 J. Exp. Med. 2013 Vol. 210 No. 9 1695-1710 www.jem.org/cgi/doi/10.1084/jem.20130579 1695 The fully human anti-cytotoxic T lymphocyte– associated antigen 4 (CTLA-4) monoclonal antibody Ipilimumab represents the irst of a new class of cancer therapies that function by enhancing immunological antitumor activity. Two pivotal phase III clinical trials demon- strated signiicant increases in survival in pa- tients with melanoma treated with Ipilimumab (Hodi et al., 2010; Robert et al., 2011), which led to its recent approval by the FDA. Despite intensive investigation, however, the mecha- nism of action remains unclear. Although the initial premise was that anti–CTLA-4 antibodies (–CTLA-4) function by blocking inhibitory signals into efector T cells (T ef cell; Krummel and Allison, 1996; Sutmuller et al., 2001), the demonstration that CD4 + Foxp3 + regulatory T cells (T reg cell) express high levels of CTLA-4 led to the suggestion that –CTLA-4 directly impacts the T reg cell compartment, either by mediating depletion, or by afecting their suppressive activity (Read et al., 2000, 2006; Takahashi et al., 2000; Wing et al., 2008). In this regard, we recently demonstrated that –CTLA-4 needs to bind both T ef and T reg cells to elicit full tumor protection (Peggs et al., 2009). CORRESPONDENCE Sergio A. Quezada: s.quezada@ucl.ac.uk OR James P. Allison: jallison@mdanderson.org Abbreviations used: ADCC, antibody-dependent cell- mediated cytotoxicity; CTLA-4, cytotoxic T lymphocyte– associated antigen 4; GVAX, granulocyte-macrophage colony- stimulating factor secreting tumor cell-based vaccine; SPR, surface plasmon resonance; T ef cell, CD4 + Foxp3  efector T cells; T reg cell, CD4 + Foxp3 + regulatory T cells. T.R. Simpson’s present address is Jounce Therapeutics, Inc. Cambridge, MA 02138. M.A. Sepulveda’s present address is Janssen Research & De- velopment, Spring House, PA 19477. Fc-dependent depletion of tumor-iniltrating regulatory T cells co-deines the eicacy of anti–CTLA-4 therapy against melanoma Tyler R. Simpson, 1,2,3 Fubin Li, 4 Welby Montalvo-Ortiz, 1 Manuel A. Sepulveda, 3 Katharina Bergerhof, 6 Frederick Arce, 6 Claire Roddie, 6 Jake Y. Henry, 6 Hideo Yagita, 5 Jedd D. Wolchok, 3 Karl S. Peggs, 6 Jefrey V. Ravetch, 4 James P. Allison, 1 and Sergio A. Quezada 6 1 Department of Immunology, MD Anderson Cancer Center, Houston, TX 77030 2 Weill Cornell Graduate School of Medical Sciences, New York, NY 10065 3 Ludwig Center for Cancer Immunotherapy, Department of Immunology, and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 4 Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065 5 Department of Immunology, Juntendo University School of Medicine, 113-8421 Tokyo, Japan 6 Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London WC1E 6DD, UK Treatment with monoclonal antibody speciic for cytotoxic T lymphocyte–associated anti- gen 4 (CTLA-4), an inhibitory receptor expressed by T lymphocytes, has emerged as an effective therapy for the treatment of metastatic melanoma. Although subject to debate, current models favor a mechanism of activity involving blockade of the inhibitory activity of CTLA-4 on both effector (T eff) and regulatory (T reg) T cells, resulting in enhanced antitumor effector T cell activity capable of inducing tumor regression. We demonstrate, however, that the activity of anti–CTLA-4 antibody on the T reg cell compartment is mediated via selective depletion of T reg cells within tumor lesions. Importantly, T reg cell depletion is dependent on the presence of Fc receptor–expressing macrophages within the tumor microenvironment, indicating that T reg cells are depleted in trans in a context- dependent manner. Our results reveal further mechanistic insight into the activity of anti-CTLA-4–based cancer immunotherapy, and illustrate the importance of speciic features of the local tumor environment on the inal outcome of antibody-based immuno- modulatory therapies. © 2013 Simpson et al. This article is distributed under the terms of an Attribution– Noncommercial–Share Alike–No Mirror Sites license for the irst six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial– Share Alike 3.0 Unported license, as described at http://creativecommons.org/ licenses/by-nc-sa/3.0/). The Journal of Experimental Medicine