College of Pharmacy, College of Public Health, University of Iowa, Iowa City, Iowa 52242, United States.
Mol Pharm. 2011 Oct 3;8(5):1652-61. doi: 10.1021/mp100464y. Epub 2011 Aug 9.
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.
佐剂调节癌症疫苗产生的保护性 CD8(+)T 细胞反应。我们之前已经表明，免疫刺激性胞嘧啶-磷酸二酯-鸟嘌呤（CpG）寡脱氧核苷酸（ODN）可显著增强给予腺病毒癌症疫苗的小鼠的肿瘤保护作用。在这里，我们研究了另一种候选疫苗佐剂壳聚糖对腺病毒癌症疫苗提供的保护作用的影响。出乎意料的是，用腺病毒癌症疫苗与壳聚糖联合免疫小鼠，对肿瘤挑战几乎没有提供保护。这与 Ag 特异性 CD8(+)T 细胞、干扰素-γ（IFN-γ）产生和细胞毒性 T 细胞活性的检测减少直接相关。我们排除了免疫抑制性调节性 T 细胞，因为无论是否给予壳聚糖，其频率都没有改变。在哺乳动物细胞系中，壳聚糖不干扰腺病毒转基因表达。然而，用壳聚糖复合的腺病毒感染原代鼠骨髓来源的树突状细胞，显著降低了细胞活力、转基因表达和主要组织相容性（MHC）I 类和 CD86 的上调。我们的体外观察表明，壳聚糖可显著抑制腺病毒介导的转基因表达和抗原呈递细胞激活，这可能阻止体内 CD8(+)T 细胞的激活。这些令人惊讶的数据首次表明，壳聚糖疫苗制剂可通过其对树突状细胞的作用，对 CD8(+)T 细胞反应的诱导产生负面影响，这在临床上很重要，因为考虑将壳聚糖作为疫苗制剂的佐剂正在增加。
