{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T03:47:20Z","timestamp":1777088840872,"version":"3.51.4"},"reference-count":33,"publisher":"Rockefeller University Press","issue":"8","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,8,3]]},"abstract":"<jats:p>Cytotoxic T lymphocyte\u2013associated antigen 4 (CTLA-4) is a critical negative regulator of immune responses. Uniquely among known inhibitory receptors, its genetic ablation results in a fulminating and fatal lymphoproliferative disorder. This central regulatory role led to the development of antibodies designed to block CTLA-4 activity in vivo, aiming to enhance immune responses against cancer. Despite their preclinical efficacy and promising clinical activity against late stage metastatic melanoma, the critical cellular targets for their activity remains unclear. In particular, debate has focused on whether the effector T cell (Teff) or regulatory T cell (T reg cell) compartment is the primary target of antibody-mediated blockade. We developed a mouse expressing human instead of mouse CTLA-4, allowing us to evaluate the independent contributions of CTLA-4 blockade of each T cell compartment during cancer immunotherapy in an in vivo model of mouse melanoma. The data show that although blockade on effector cells significantly improves tumor protection, unicompartmental blockade on regulatory cells completely fails to enhance antitumor responses. However, concomitant blockade of both compartments leads to a synergistic effect and maximal antitumor activity. We conclude that the combination of direct enhancement of Teff cell function and concomitant inhibition of T reg cell activity through blockade of CTLA-4 on both cell types is essential for mediating the full therapeutic effects of anti\u2013CTLA-4 antibodies during cancer immunotherapy.<\/jats:p>","DOI":"10.1084\/jem.20082492","type":"journal-article","created":{"date-parts":[[2009,7,6]],"date-time":"2009-07-06T21:28:41Z","timestamp":1246915721000},"page":"1717-1725","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":815,"title":["Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti\u2013CTLA-4 antibodies"],"prefix":"10.1084","volume":"206","author":[{"given":"Karl S.","family":"Peggs","sequence":"first","affiliation":[{"name":"Ludwig Center for Cancer Immunotherapy, Howard Hughes Medical Institute, Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021 1"}]},{"given":"Sergio A.","family":"Quezada","sequence":"additional","affiliation":[{"name":"Ludwig Center for Cancer Immunotherapy, Howard Hughes Medical Institute, Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021 1"}]},{"given":"Cynthia A.","family":"Chambers","sequence":"additional","affiliation":[{"name":"Department of Pathology, Graduate Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, MA 01655 2"}]},{"given":"Alan J.","family":"Korman","sequence":"additional","affiliation":[{"name":"Medarex, Inc., Milpitas, CA 95035 3"}]},{"given":"James P.","family":"Allison","sequence":"additional","affiliation":[{"name":"Ludwig Center for Cancer Immunotherapy, Howard Hughes Medical Institute, Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021 1"}]}],"member":"291","published-online":{"date-parts":[[2009,7,6]]},"reference":[{"key":"2023072917264604700_bib2","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.4049\/jimmunol.163.3.1128","article-title":"Cutting edge: lymphoproliferative disease in the absence of CTLA-4 is not T cell autonomous","volume":"163","author":"Bachmann","year":"1999","journal-title":"J. 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