Induction of antitumor immunity ex vivo using dendritic cells transduced with fowl pox vector expressing MUC1, CEA, and a triad of costimulatory molecules (rF-PANVAC).
The fowl pox vector expressing the tumor-associated antigens, mucin-1 and carcinoembryonic antigen in the context of costimulatory molecules (rF-PANVAC) has shown promise as a tumor vaccine. However, vaccine-mediated expansion of suppressor T-cell populations may blunt clinical efficacy. We characterized the cellular immune response induced by ex vivo dendritic cells (DCs) transduced with (rF)-PANVAC. Consistent with the functional characteristics of potent antigen-presenting cells, rF-PANVAC-DCs demonstrated strong expression of mucin-1 and carcinoembryonic antigen and costimulatory molecules, CD80, CD86, and CD83; decreased levels of phosphorylated STAT3, and increased levels of Tyk2, Janus kinase 2, and STAT1. rF-PANVAC-DCs stimulated expansion of tumor antigen-specific T cells with potent cytolytic capacity. However, rF-PANVAC-transduced DCs also induced the concurrent expansion of FOXP3 expressing CD4CD25 regulatory T cells (Tregs) that inhibited T-cell activation. Moreover, Tregs expressed high levels of Th2 cytokines [interleukin (IL)-10, IL-4, IL-5, and IL-13] together with phosphorylated STAT3 and STAT6. In contrast, the vaccine-expanded Treg population expressed high levels of Th1 cytokines IL-2 and interferon-γ and the proinflammatory receptor-related orphan receptor γt (RORγt) and IL-17A suggesting that these cells may share effector functions with conventional TH17 T cells. These data suggest that Tregs expanded by rF-PANVAC-DCs, exhibit immunosuppressive properties potentially mediated by Th2 cytokines, but simultaneous expression of Th1 and Th17-associated factors suggests a high degree of plasticity.
Dana-Farber Cancer Institute, Center for Molecular Orthopaedics, Brigham & Women's Hospital, Boston, MA, USA.
Baldev
B
Vasir
Corrine
C
Zarwan
Rehan
R
Ahmad
Keith D
KD
Crawford
Hassan
H
Rajabi
Ken-Ichi
K
Matsuoka
Jacalyn
J
Rosenblatt
Zekui
Z
Wu
Heidi
H
Mills
Donald
D
Kufe
David
D
Avigan
D015704:CD4 Antigens / Q000378:metabolism; D019496:Cancer Vaccines / Q000235:genetics / Q000378:metabolism*; D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005587:Fowlpox virus; D005822:Genetic Vectors; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058408:Th1-Th2 Balance; D058504:Th17 Cells / Q000276:immunology*; D014161:Transduction, Genetic
D015704:CD4 Antigens; D019496:Cancer Vaccines; D002272:Carcinoembryonic Antigen; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D008562:Membrane Glycoproteins; D018396:Mucin-1; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C518274:Panvac-VF; D050791:STAT Transcription Factors