Laboratory for Molecular Microbiology (LMM), Institute of Molecular Genetics and Genetic Engineering (IMGGI), University of Belgrade, Belgrade, Serbia.
Department for Immunology and Immunoparasitology, Institute for the Application of Nuclear Energy, University of Belgrade, Belgrade, Serbia.
Gut Microbes. 2021 Jan-Dec;13(1):1-20. doi: 10.1080/19490976.2021.1921927.
Although promising for active immunization in cancer patients, dendritic cells (DCs) vaccines generated display high inter-individual variability in their immunogenicity, which mostly limits their therapeutic efficacy. Gut microbiota composition is a key emerging factor affecting individuals' immune responses, but it is unknown how it affects the variability of donors' precursor cells to differentiate into immunogenic DCs . By analyzing gut microbiota composition in 14 healthy donors, along with the phenotype and cytokines production by monocyte-derived DCs, we found significant correlations between immunogenic properties of DC and microbiota composition. Namely, donors who had higher α-diversity of gut microbiota and higher abundance of short-chain fatty acid (SCFAs) and SCFA-producing bacteria in feces, displayed lower expression of CD1a on immature (im)DC and higher expression of ILT-3, costimulatory molecules (CD86, CD40) proinflammatory cytokines (TNF-α, IL-6, IL-8) and IL-12p70/IL-10 ratio, all of which correlated with their lower maturation potential and immunogenicity upon stimulation with LPS/IFNγ, a well-known Th1 polarizing cocktail. In contrast, imDCs generated from donors with lower α-diversity and higher abundance of and in feces displayed higher CD1a expression and higher potential to up-regulate CD86 and CD40, increase TNF-α, IL-6, IL-8 production, and IL-12p70/IL-10 ratio upon stimulation. These results emphasize the important role of gut microbiota on the capacity of donor precursor cells to differentiate into immunogenic DCs suitable for cancer therapy, which could be harnessed for improving the actual and future DC-based cancer therapies.
尽管树突状细胞 (DC) 疫苗在癌症患者的主动免疫中很有前景，但它们的免疫原性在个体间存在很大的变异性，这主要限制了它们的治疗效果。肠道微生物群落组成是影响个体免疫反应的一个关键新兴因素，但尚不清楚它如何影响供体前体细胞分化为免疫原性 DC 的变异性。通过分析 14 名健康供体的肠道微生物群落组成，以及单核细胞来源的 DC 的表型和细胞因子产生，我们发现 DC 的免疫原性与微生物群落组成之间存在显著相关性。即，具有较高肠道微生物 α 多样性和粪便中短链脂肪酸 (SCFA) 及产生 SCFA 的细菌丰度较高的供体，其不成熟 (im)DC 上的 CD1a 表达较低，而 ILT-3、共刺激分子 (CD86、CD40)、促炎细胞因子 (TNF-α、IL-6、IL-8) 和 IL-12p70/IL-10 比值较高，所有这些都与它们在 LPS/IFNγ刺激下的较低成熟潜能和免疫原性相关，LPS/IFNγ 是一种众所周知的 Th1 极化鸡尾酒。相比之下，来自 α 多样性较低和粪便中 丰度较高的供体的 imDC 表现出较高的 CD1a 表达和更高的上调 CD86 和 CD40、增加 TNF-α、IL-6、IL-8 产生以及 IL-12p70/IL-10 比值的潜力。这些结果强调了肠道微生物群对供体前体细胞分化为适合癌症治疗的免疫原性 DC 的能力的重要作用，这可以用于改善当前和未来基于 DC 的癌症治疗。
