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Blood, 15 August 2008, Vol. 112, No. 4, pp. 1175-1183. Prepublished online as a Blood First Edition Paper on June 3, 2008; DOI 10.1182/blood-2007-11-125435. This Article Full Text (PDF) All Versions of this Article: blood-2007-11-125435v1 112/4/1175    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kavanagh, B. Articles by Fong, L. Search for Related Content PubMed PubMed Citation Articles by Kavanagh, B. Articles by Fong, L. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 27, 2007 Accepted March 27, 2008 CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependant fashion Brian Kavanagh, Shaun O'Brien, David Lee, Yafei Hou, Vivian Weinberg, Brian Rini, James P Allison, Eric J Small, and Lawrence Fong* Division of Hematology/Oncology, UCSF, San Francisco, CA, United States Department of Microbiology and Immunology, UCSF, San Francisco, CA, United States Department of Biostatistics, UCSF, San Francisco, CA, United States Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, United States * Corresponding author; email: lfong{at}medicine.ucsf.edu. CTL-associated antigen 4 (CTLA4) delivers inhibitory signals to activated T cells. CTLA4 is constitutively expressed on regulatory CD4+ T cells (Tregs), but its role in these cells remains unclear. CTLA4 blockade with a monoclonal treatment has been shown to induce antitumor immunity in preclinical and early clinical trials. In this study, we examine the effects of increasing doses of anti-CTLA4 antibody on the endogenous CD4+ T cells in cancer patients. We show that CTLA4 blockade induces not only an increase in the number of activated effector CD4+ T cells, but also increases the number of CD4+ FoxP3+ Tregs. While the effects were dose-dependent, CD4+ FoxP3+ regulatory T cells could be expanded at lower antibody doses. In contrast, expansion of effector T cells was only seen at the highest dose level studied. Moreover, these expanded CD4+ FoxP3+ regulatory T cells are induced to proliferate with treatment and possess suppressor function. Our results demonstrate that treatment with anti-CTLA4 antibody does not deplete human CD4+ FoxP3+ Tregs in vivo, but rather may mediate its effects through the activation of effector T cells. Our results also suggest that CTLA4 may inhibit Treg proliferation similar to its role on effector T cells. This study is registered at http://www.clinicaltrials.gov/ct2/show/NCT00064129, registry number NCT00064129. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C Coquerelle, G Oldenhove, V Acolty, J Denoeud, G Vansanten, J-M Verdebout, A Mellor, J A Bluestone, and M Moser Anti-CTLA-4 treatment induces IL-10-producing ICOS+ regulatory T cells displaying IDO-dependent anti-inflammatory properties in a mouse model of colitis Gut, October 1, 2009; 58(10): 1363 - 1373. [Abstract] [Full Text] [PDF] J. Verhagen, L. Gabrysova, S. Minaee, C. A. Sabatos, G. Anderson, A. H. Sharpe, and D. C. Wraith Enhanced selection of FoxP3+ T-regulatory cells protects CTLA-4-deficient mice from CNS autoimmune disease PNAS, March 3, 2009; 106(9): 3306 - 3311. [Abstract] [Full Text] [PDF] L. Fong, S. S. Kwek, S. O'Brien, B. Kavanagh, D. G. McNeel, V. Weinberg, A. M. Lin, J. Rosenberg, C. J. Ryan, B. I. Rini, et al. Potentiating Endogenous Antitumor Immunity to Prostate Cancer through Combination Immunotherapy with CTLA4 Blockade and GM-CSF Cancer Res., January 15, 2009; 69(2): 609 - 615. [Abstract] [Full Text] [PDF] J. L. Marshall Time to Shift the Focus of the War: It Is Not All About the Enemy J. Clin. Oncol., January 10, 2009; 27(2): 168 - 169. [Full Text] [PDF] E. M. Schmidt, C. J. Wang, G. A. Ryan, L. E. Clough, O. S. Qureshi, M. Goodall, A. K. Abbas, A. H. Sharpe, D. M. Sansom, and L. S. K. Walker CTLA-4 Controls Regulatory T Cell Peripheral Homeostasis and Is Required for Suppression of Pancreatic Islet Autoimmunity J. Immunol., January 1, 2009; 182(1): 274 - 282. [Abstract] [Full Text] [PDF] L. Fong and E. J. Small Anti-Cytotoxic T-Lymphocyte Antigen-4 Antibody: The First in an Emerging Class of Immunomodulatory Antibodies for Cancer Treatment J. Clin. Oncol., November 10, 2008; 26(32): 5275 - 5283. [Abstract] [Full Text] [PDF]

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