Type 2 Bias of T cells expanded from the blood of melanoma patients switched to type 1 by IL-12p70 mRNA-transfected dendritic cells.
Melanoma patients may exhibit a T(H)2-skewed cytokine profile within blood and tumor-infiltrating lymphocytes. Therapies that induce beneficial T(H)1-type tumor-specific immune responses, therefore, are highly desirable. Dendritic cells (DC) are widely used as immune adjuvants for cancer. Before their administration, DC are generally induced to mature with a cocktail of recombinant cytokines [interleukin (IL)-1beta, tumor necrosis factor alpha, and IL-6] and prostaglandin E(2) (PGE(2)), which is added to preserve the ability of DC to migrate to draining lymph nodes. However, PGE(2) suppresses the production of IL-12p70, a cytokine essential for differentiation of T(H)1 responses. In this study, human DC were transfected with IL-12p70 mRNA and tested for their ability to alter the T(H)2 type bias manifested by blood T cells of patients with melanoma. Transfected DC secreted high levels of bioactive IL-12p70, as indicated by their capacity to enhance natural killer cell activity, skew T(H)1 responses in allogeneic mixed lymphocyte reactions through reduction of IL-4 and IL-5, and prime CD8(+) T cells to the melanoma-associated antigen Melan A/MART-1. Furthermore, T-cell lines primed in vitro from the blood of melanoma patients showed strong type 2 skewing that was dramatically reversed by IL-12p70 transfection of autologous DC. Thus, IL-12p70 transfection of clinical DC preparations may enhance type 1 antitumor responses and may thereby contribute to effective immune-based therapy.
Minkis
Kira
K
New York University School of Medicine, New York, USA.
Kavanagh
Daniel G
DG
Alter
Galit
G
Bogunovic
Dusan
D
O'Neill
David
D
Adams
Sylvia
S
Pavlick
Anna
A
Walker
Bruce D
BD
Brockman
Mark A
MA
Gandhi
Rajesh T
RT
Bhardwaj
Nina
N
D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000502:physiology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000235:genetics / Q000502:physiology*; D015848:Interleukin-5 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D014162:Transfection
D000951:Antigens, Neoplasm; D015848:Interleukin-5; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D018664:Interleukin-12; D007371:Interferon-gamma