Stimulation of human T cells by an influenza A vector expressing a CTL epitope from the HER-2/neu protooncogene results in higher numbers of antigen-specific TCRhi cells than stimulation with peptide. Divergent roles of IL-2 and IL-15.
Development of cancer vaccines requires approaches to induce expansion and functional differentiation of tumor antigen-specific effector and memory cells. The later are particularly relevant for prevention of disease relapse. Efficient induction of memory cells is hindered by the lack of information about the relationship between TCR stimulation and the cytokines required for Ag-specific memory CD8+ cells and proliferation and survival. Since viruses are known to induce memory T cells, an attenuated influenza A/PR8/34 virus with a truncated nonstructural (NS1) gene was generated containing the HER-2 CTL E75 epitope in its neuraminidase protein (KIF-NS virus). Stimulation of PBMC from healthy donors and of tumor-associated lymphocytes (TAL) from ovarian cancer patients with dendritic cells (DC) infected with KIF-NS (KIF-NS-DC), induced higher numbers of immediate memory effector CD8+ CD44hi CD122hi cells, expressing TCR specific for E75 (E75-TCR) than stimulation with peptide E75. Survival of CD44hi CD122hi cells was dependent on the levels of TCR; cells expressing lower levels of E75-TCR (MFI: 10(2)-10(3)) survived better in IL-2 while cells expressing high levels of TCR (MFI: 10(3)-10(4)) survived better in IL-15. This is the first report demonstrating induction of human Ag-specific memory CD8+ cells against a human tumor-antigen using a live attenuated recombinant influenza virus vector. Such vectors may provide a novel approach for preventive immunity in human cancer vaccine development.
Efferson
Clay L
CL
Department of Gynecologic Oncology, M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Kawano
Kouichiro
K
Tsuda
Naotake
N
Palese
Peter
P
García-Sastre
Adolfo
A
Ioannides
Constantin G
CG
D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D018734:Genes, erbB-2 / Q000276:immunology*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology; D009980:Influenza A virus / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D019409:Interleukin-15 / Q000276:immunology* / Q000494:pharmacology; D007376:Interleukin-2 / Q000276:immunology* / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000276:immunology; D010455:Peptides / Q000276:immunology / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D015854:Up-Regulation; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology
D018984:Epitopes, T-Lymphocyte; D018960:Hyaluronan Receptors; D007371:Interferon-gamma; D019409:Interleukin-15; D007376:Interleukin-2; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D017361:Viral Nonstructural Proteins; C085820:INS1 protein, influenza virus