title: Chitosan is a surprising negative modulator of cytotoxic CD8+ T cell responses elicited by adenovirus cancer vaccines.
abstract: Adjuvants modulate protective CD8(+) T cell responses generated by cancer vaccines. We have previously shown that immunostimulatory cytosine-phosphodiester-guanine (CpG) oligodeoxynucleotide (ODN) significantly augments tumor protection in mice given adenovirus cancer vaccines. Here, we examined the impact of chitosan, another candidate vaccine adjuvant, on protection conferred by adenovirus cancer vaccines. Unexpectedly, immunization of mice with adenovirus cancer vaccines in combination with chitosan provided little protection against tumor challenge. This directly correlated with the reduced detection of Ag-specific CD8(+) T cells, interferon-γ (IFN-γ) production, and cytotoxic T cell activity. We ruled out immunosuppressive regulatory T cells since the frequency did not change regardless of whether chitosan was delivered. In mammalian cell lines, chitosan did not interfere with adenovirus transgene expression. However, infection of primary murine bone marrow-derived dendritic cells with adenovirus complexed with chitosan significantly reduced viability, transgene expression, and upregulation of major histocompatability (MHC) class I and CD86. Our in vitro observations indicate that chitosan dramatically inhibits adenovirus-mediated transgene expression and antigen presenting cell activation, which could prevent CD8(+) T cell activation from occurring in vivo. These surprising data demonstrate for the first time that chitosan vaccine formulations can negatively impact the induction of CD8(+) T cell responses via its effect on dendritic cells, which is clinically important since consideration of chitosan as an adjuvant for vaccine formulations is growing.
authors.affiliation: College of Pharmacy, College of Public Health, University of Iowa, Iowa City, Iowa 52242, United States.
authors.forename: Caitlin D
authors.initials: CD
authors.lastname: Lemke
authors.forename: Jessica B
authors.initials: JB
authors.lastname: Graham
authors.forename: Sean M
authors.initials: SM
authors.lastname: Geary
authors.forename: Gideon
authors.initials: G
authors.lastname: Zamba
authors.forename: David M
authors.initials: DM
authors.lastname: Lubaroff
authors.forename: Aliasger K
authors.initials: AK
authors.lastname: Salem
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D051940:B7-2 Antigen / Q000378:metabolism; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D019496:Cancer Vaccines / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D048271:Chitosan / Q000633:toxicity*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015536:Down-Regulation / Q000187:drug effects*; D005814:Genes, Viral / Q000187:drug effects; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D007155:Immunologic Factors / Q000633:toxicity*; D059425:Interferon-gamma Release Tests; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D019076:Transgenes / Q000187:drug effects
chemical_list: D051940:B7-2 Antigen; D019496:Cancer Vaccines; C497965:Cd86 protein, mouse; D015395:Histocompatibility Antigens Class I; D007155:Immunologic Factors; D048271:Chitosan