Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells
Jens Dannull, Zhen Su, David Rizzieri, Benjamin K. Yang, Doris Coleman, Donna Yancey, Aijing Zhang, Philipp Dahm, Nelson Chao, Eli Gilboa, Johannes Vieweg
Jens Dannull, Zhen Su, David Rizzieri, Benjamin K. Yang, Doris Coleman, Donna Yancey, Aijing Zhang, Philipp Dahm, Nelson Chao, Eli Gilboa, Johannes Vieweg
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Research Article Immunology

Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells

Abstract

In this study, we investigated whether elimination of CD4+/CD25+ Tregs using the recombinant IL-2 diphtheria toxin conjugate DAB389IL-2 (also known as denileukin diftitox and ONTAK) is capable of enhancing the immunostimulatory efficacy of tumor RNA-transfected DC vaccines. We show that DAB389IL-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. DAB389IL-2–mediated Treg depletion resulted in enhanced stimulation of proliferative and cytotoxic T cell responses in vitro but only when DAB389IL-2 was omitted during T cell priming. DAB389IL-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, DAB389IL-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.

Authors

Jens Dannull, Zhen Su, David Rizzieri, Benjamin K. Yang, Doris Coleman, Donna Yancey, Aijing Zhang, Philipp Dahm, Nelson Chao, Eli Gilboa, Johannes Vieweg

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In vivo induction and cytokine profile of RCC-specific CD4+ T cell respo...
In vivo induction and cytokine profile of RCC-specific CD4+ T cell responses. (A) CD4+ T cells were isolated from pre- (white bars) and post-vaccination (black bars) PBMC samples of 3 study subjects (representative data from patient RCC-01-DAB are shown) who received DAB389IL-2 (18 μg/kg) followed by vaccination with RCC RNA-transfected DCs (2 cycles of 1 × 107 cells per treatment). Cells were stimulated for 18 hours with autologous PBMC RNA-, RE RNA-, or RCC RNA-transfected DCs. IFN-γ (left panel) or IL-4–expressing T cells (right panel) were enumerated using an automated ELISPOT reader, and antigen-specific T cell frequencies were expressed as the number of spot-forming cells per 1 × 105 CD4+ T cells. Staphylococcal enterotoxin B (SEB) at a concentration of 10 μg/ml was used as a positive control in the IL-4 ELISPOT assays (right panel). (B) The cytokine expression profile of CD4+ T cells prior to (gray) and after (white) vaccination was measured after overnight (18 hours) stimulation with RCC (DC+RCC) or RE RNA-transfected DCs (DC+RE) using human Th1/Th2 cytometric bead arrays. Culture supernatants were used to determine expression of the Th-1 cytokines IFN-γ, TNF-α, and IL-2 as well as the Th-2 type cytokines IL-4 and IL-10.