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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.
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IMMUNOBIOLOGY
CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion
Brian Kavanagh1,2,
Shaun O'Brien1,2,
David Lee1,2,
Yafei Hou1,2,
Vivian Weinberg3,
Brian Rini1,
James P. Allison4,
Eric J. Small1, and
Lawrence Fong1,2
1 Division of Hematology/Oncology,
2 Department of Microbiology and Immunology, and
3 Department of Biostatistics, University of California, San Francisco; and
4 Ludwig Center for Cancer Immunotherapy, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY
Cytotoxic T lymphocyte–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 has been shown to induce antitumor immunity. In this study, we examined the effects of anti-CTLA4 antibody on the endogenous CD4+ T cells in cancer patients. We show that CTLA4 blockade induces an increase not only in the number of activated effector CD4+ T cells, but also in the number of CD4+ FoxP3+ Tregs. Although 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 seen only 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
[ClinicalTrials.gov]
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