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).

Abstract

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.

• Authors: Baldev Vasir, Corrine Zarwan, Rehan Ahmad, Keith D Crawford, Hassan Rajabi, Ken-Ichi Matsuoka, Jacalyn Rosenblatt, Zekui Wu, Heidi Mills, Donald Kufe, David Avigan
• Journal: Journal of immunotherapy (Hagerstown, Md. : 1997) (J Immunother) Vol. 35 Issue 7 Pg. 555-69 (Sep 2012) ISSN: 1537-4513 [Electronic] United States
• PMID: 22892452 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• CD4 Antigens
• Cancer Vaccines
• Carcinoembryonic Antigen
• Cytokines
• FOXP3 protein, human
• Forkhead Transcription Factors
• Interleukin-2 Receptor alpha Subunit
• Membrane Glycoproteins
• Mucin-1
• Nuclear Receptor Subfamily 1, Group F, Member 3
• Panvac-VF
• STAT Transcription Factors

Topics

• CD4 Antigens (metabolism)
• Cancer Vaccines (genetics, metabolism)
• Carcinoembryonic Antigen (genetics, metabolism)
• Cells, Cultured
• Cytokines (metabolism)
• Dendritic Cells (immunology, metabolism, virology)
• Forkhead Transcription Factors (metabolism)
• Fowlpox virus
• Genetic Vectors
• Humans
• Interleukin-2 Receptor alpha Subunit (metabolism)
• Lymphocyte Activation
• Membrane Glycoproteins (genetics, metabolism)
• Mucin-1 (genetics, metabolism)
• Nuclear Receptor Subfamily 1, Group F, Member 3 (genetics, metabolism)
• STAT Transcription Factors (genetics, metabolism)
• T-Lymphocytes, Cytotoxic (immunology)
• T-Lymphocytes, Regulatory (immunology)
• Th1-Th2 Balance
• Th17 Cells (immunology)
• Transduction, Genetic