Tumor Immunobiology Program of the James Graham Brown Cancer Center, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.
Clin Cancer Res. 2010 Nov 1;16(21):5153-64. doi: 10.1158/1078-0432.CCR-10-0820. Epub 2010 Sep 20.
The beneficial properties of β-glucans have been recognized for centuries. Their proposed mechanisms of action in cancer therapy occur via stimulation of macrophages and priming of innate neutrophil complement receptor 3 for eliciting complement receptor 3-dependent cellular cytotoxicity of iC3b-opsonized tumor cells. The current study is to investigate whether β-glucan therapy has any effect on antitumor adaptive T-cell responses.
We first examined the trafficking of orally administered particulate yeast-derived β-glucan and its interaction with dendritic cells (DC) that captured tumor materials. Antigen-specific T cells were adoptively transferred into recipient mice to determine whether oral β-glucan therapy induces augmented T-cell responses. Lewis lung carcinoma and RAM-S lymphoma models were used to test oral β-glucan therapeutic effect. Further mechanistic studies including tumor-infiltrating T cells and cytokine profiles within the tumor milieu were determined.
Orally administered particulate β-glucan trafficked into spleen and lymph nodes and activated DCs that captured dying tumor cells in vivo, leading to the expansion and activation of antigen-specific CD4 and CD8 T cells. In addition, IFN-γ production of tumor-infiltrating T cells and CTL responses were significantly enhanced on β-glucan treatment, which ultimately resulted in significantly reduced tumor burden. Moreover, β-glucan-treated tumors had significantly more DC infiltration with the activated phenotype and significant levels of Th1-biased cytokines within the tumor microenvironment.
These data highlight the ability of yeast-derived β-glucan to bridge innate and adaptive antitumor immunity and suggest that it can be used as an adjuvant for tumor immunotherapy.
β-葡聚糖的有益特性已被人们认识了几个世纪。其在癌症治疗中的作用机制是通过刺激巨噬细胞和预先激活先天中性粒细胞补体受体 3，从而引发补体受体 3 依赖性细胞毒性，使 iC3b 包被的肿瘤细胞对其敏感。本研究旨在探讨β-葡聚糖治疗是否对抗肿瘤适应性 T 细胞反应有影响。
我们首先研究了口服给予的颗粒状酵母衍生β-葡聚糖的转运及其与捕获肿瘤物质的树突状细胞（DC）的相互作用。将抗原特异性 T 细胞过继转移到受体小鼠中，以确定口服β-葡聚糖治疗是否会引起增强的 T 细胞反应。使用 Lewis 肺癌和 RAM-S 淋巴瘤模型来测试口服β-葡聚糖的治疗效果。进一步的机制研究包括肿瘤浸润性 T 细胞和肿瘤微环境中的细胞因子谱。
口服给予的颗粒状β-葡聚糖在体内转运到脾脏和淋巴结，并激活了 DC，后者捕获了死亡的肿瘤细胞，导致抗原特异性 CD4 和 CD8 T 细胞的扩增和激活。此外，β-葡聚糖治疗后肿瘤浸润性 T 细胞的 IFN-γ产生和 CTL 反应显著增强，最终导致肿瘤负担显著减轻。此外，β-葡聚糖治疗的肿瘤具有更多浸润的 DC，其具有激活表型，并且肿瘤微环境中存在明显的 Th1 偏向性细胞因子。
这些数据突出了酵母衍生β-葡聚糖桥接先天和适应性抗肿瘤免疫的能力，并表明它可作为肿瘤免疫治疗的佐剂。
