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 CpG 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 reduced detection of Ag-specific CD8+ T cells, IFN-γ production and cytotoxic T cell activity. We ruled out immunosuppressive regulatory T cells since 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 MHC class I and CD86. Our in vitro observations indicate that chitosan dramatically inhibits adenovirus-mediated transgene expression and antigen presenting cell activation, without which CD8+ T cell activation cannot occur 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.

Biodegradable particles as vaccine antigen delivery systems for stimulating cellular immune responses

“…77 In a tumor protection study performed in our laboratory we observed that, in contrast to expectations, low molecular weight chitosan complexed with adenovirus encoding a model tumor Ag actually reduced Ag-specific CD8 + T-cell levels and consequently mice vaccinated subcutaneously with these complexes were more susceptible to subsequent tumor challenge than mice vaccinated with adenovirus alone. 78 We also discovered that chitosan when complexed with adenovirus interfered with transduction of bone marrow derived dendritic cells (but not other cell types) in vitro. It is possible therefore that chitosan may not be an ideal adjuvant for adenoviral vaccines delivered via non mucosal routes, particularly if strong cytotoxic T-cell responses are desired over humoral responses.…”

Antigen-coated poly α-hydroxy acid based microparticles for heterologous prime-boost adenovirus based vaccinations

“…Boost immunizations consisted of either PBS or 10 8 pfu of adenovirus encoding tumor Ag. OVA-encoding, replication-deficient adenovirus serotype 5 (AdOVA) was obtained from the University of Iowa Gene Transfer Vector Core, as previously described [14, 15]. …”

Carbohydrate-Based Adjuvants for Vaccine Production

“…Но при исследовании вакцин про-тив рака были выявлены и отрицательные эффекты хитозана. У мышей аденовирусная вакцина против рака в комбинации с хитозаном в качестве адъюванта приводила к снижению ак-тивности антиген-специфичных CD8 + T-клеток, ЦТЛ и уменьше-нию выработки IFN-γ [59]. Причиной этому послужило ингиби-рование хитозаном опосредованной аденовирусом экспрессии трансгена и активности АПК.…”