CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4 + T cells in a dose-dependent fashion Journal Article
| Authors: | Kavanagh, B.; O'Brien, S.; Lee, D.; Hou, Y.; Weinberg, V.; Rini, B.; Allison, J. P.; Small, E. J.; Fong, L. |
| Article Title: | CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4 + T cells in a dose-dependent fashion |
| Abstract: | 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.clinicattrials.gov/ct2/show/NCT00064129, registry number NCT00064129. © 2008 by The American Society of Hematology. |
| Keywords: | adult; controlled study; aged; aged, 80 and over; middle aged; clinical trial; antineoplastic agent; ki 67 antigen; transcription factor foxp3; cell proliferation; ki-67 antigen; cell function; cytotoxic t lymphocyte antigen 4 antibody; ipilimumab; metastasis; antineoplastic combined chemotherapy protocols; granulocyte macrophage colony stimulating factor; in vivo study; enzyme activation; drug effect; pathology; drug dose escalation; prostate cancer; prostatic neoplasms; regulatory t lymphocyte; immunology; lymphocyte activation; enzyme regulation; t-lymphocytes, regulatory; prostate tumor; cd4+ t lymphocyte; cd4-positive t-lymphocytes; neoplasm metastasis; cell count; phase 1 clinical trial; antibodies; antigens, cd; cytotoxic t lymphocyte antigen 4; cell activation; antibody; leukocyte antigen; cell expansion; recombinant granulocyte macrophage colony stimulating factor; lymphocyte count; cytotoxic t-lymphocyte antigen 4; granulocyte-macrophage colony-stimulating factor |
| Journal Title: | Blood |
| Volume: | 112 |
| Issue: | 4 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2008-08-15 |
| Start Page: | 1175 |
| End Page: | 1183 |
| Language: | English |
| DOI: | 10.1182/blood-2007-11-125435 |
| PUBMED: | 18523152 |
| PROVIDER: | scopus |
| PMCID: | PMC2515138 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 43" - "Export Date: 17 November 2011" - "CODEN: BLOOA" - "Source: Scopus" |
