NSU-MD Faculty Articles
Title
Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells.
ISBN or ISSN
0021-9738
Publication Title
The Journal of clinical investigation
Volume
115
Issue
12
Publication Date / Copyright Date
12-1-2005
First Page
3623
Last Page
3633
Publisher
American Society for Clinical Investigation
DOI Number
10.1172/JCI25947
Abstract
In this study, we investigated whether elimination of CD4+/CD25+ Tregs using the recombinant IL-2 diphtheria toxin conjugate DAB(389)IL-2 (also known as denileukin diftitox and ONTAK) is capable of enhancing the immunostimulatory efficacy of tumor RNA-transfected DC vaccines. We show that DAB(389)IL-2 is capable of selectively eliminating CD25-expressing Tregs from the PBMCs of cancer patients without inducing toxicity on other cellular subsets with intermediate or low expression of CD25. DAB(389)IL-2-mediated Treg depletion resulted in enhanced stimulation of proliferative and cytotoxic T cell responses in vitro but only when DAB(389)IL-2 was omitted during T cell priming. DAB(389)IL-2 significantly reduced the number of Tregs present in the peripheral blood of metastatic renal cell carcinoma (RCC) patients and abrogated Treg-mediated immunosuppressive activity in vivo. Moreover, DAB(389)IL-2-mediated elimination of Tregs followed by vaccination with RNA-transfected DCs significantly improved the stimulation of tumor-specific T cell responses in RCC patients when compared with vaccination alone. Our findings may have implications in the design of immune-based strategies that may incorporate the Treg depletion strategy to achieve potent antitumor immunity with therapeutic impact.
Disciplines
Medicine and Health Sciences
Keywords
Aged, Antigens, Neoplasm, CD28 Antigens, CD3 Complex, CD4-Positive T-Lymphocytes, Cancer Vaccines, Carcinoma, Renal Cell, Cell Separation, Dendritic Cells, Diphtheria Toxin, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Humans, Immunosuppressive Agents, Interferon-gamma, Interleukin-2, Interleukin-4, Kidney Neoplasms, Leukocytes, Mononuclear, Male, Middle Aged, Neoplasm Metastasis, Neoplasms, RNA, RNA, Neoplasm, Receptors, Interleukin-2, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes, T-Lymphocytes, Regulatory, Time Factors, Transfection
NSUWorks Citation
Dannull, Jens; Su, Zhen; Rizzieri, David; Yang, Benjamin K; Coleman, Doris; Yancey, Donna; Zhang, Aijing; Dahm, Philipp; Chao, Nelson; Gilboa, Eli; and Vieweg, Johannes, "Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells." (2005). NSU-MD Faculty Articles. 36.
https://nsuworks.nova.edu/hpd_md_facarticles/36
