CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion.
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.
Department of Microbiology and Immunology, Division of Hematology/Oncology, University of California, San Francisco, CA 94143, USA.
Brian
B
Kavanagh
Shaun
S
O'Brien
David
D
Lee
Yafei
Y
Hou
Vivian
V
Weinberg
Brian
B
Rini
James P
JP
Allison
Eric J
EJ
Small
Lawrence
L
Fong
D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies / Q000008:administration & dosage* / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects*; D060908:CTLA-4 Antigen; D049109:Cell Proliferation / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage*; D006801:Humans; D019394:Ki-67 Antigen; D008213:Lymphocyte Activation / Q000187:drug effects*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*
D000906:Antibodies; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019394:Ki-67 Antigen; D016178:Granulocyte-Macrophage Colony-Stimulating Factor