Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells.
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.
Dannull
Jens
J
Genitourinary Cancer Immunotherapy Program, Duke University Medical Center, Durham, North Carolina 27710, USA.
Su
Zhen
Z
Rizzieri
David
D
Yang
Benjamin K
BK
Coleman
Doris
D
Yancey
Donna
D
Zhang
Aijing
A
Dahm
Philipp
P
Chao
Nelson
N
Gilboa
Eli
E
Vieweg
Johannes
J
D000368:Aged; D000951:Antigens, Neoplasm / Q000737:chemistry; D018106:CD28 Antigens / Q000096:biosynthesis; D017252:CD3 Complex / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines; D002292:Carcinoma, Renal Cell / Q000628:therapy; D002469:Cell Separation; D003713:Dendritic Cells / Q000276:immunology; D004167:Diphtheria Toxin / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007680:Kidney Neoplasms / Q000628:therapy; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D012313:RNA / Q000737:chemistry / Q000378:metabolism; D012334:RNA, Neoplasm / Q000737:chemistry; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013997:Time Factors; D014162:Transfection
D000951:Antigens, Neoplasm; D018106:CD28 Antigens; D017252:CD3 Complex; D019496:Cancer Vaccines; D004167:Diphtheria Toxin; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D012334:RNA, Neoplasm; D015375:Receptors, Interleukin-2; D015847:Interleukin-4; D012313:RNA; D007371:Interferon-gamma