Karaman Irem, Pathak Asmita, Bayik Defne, Watson Dionysios C
Bahcesehir University School of Medicine, Istanbul, Turkey.
Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Florida.
Pathog Immun. 2024 Apr 23;9(1):56-90. doi: 10.20411/pai.v9i1.657. eCollection 2024.
There are a growing number of studies linking the composition of the human microbiome to disease states and treatment responses, especially in the context of cancer. This has raised significant interest in developing microbes and microbial products as cancer immunotherapeutics that mimic or recapitulate the beneficial effects of host-microbe interactions. Bacterial extracellular vesicles (bEVs) are nano-sized, membrane-bound particles secreted by essentially all bacteria species and contain a diverse bioactive cargo of the producing cell. They have a fundamental role in facilitating interactions among cells of the same species, different microbial species, and even with multicellular host organisms in the context of colonization (microbiome) and infection. The interaction of bEVs with the immune system has been studied extensively in the context of infection and suggests that bEV effects depend largely on the producing species. They thus provide functional diversity, while also being nonreplicative, having inherent cell-targeting qualities, and potentially overcoming natural barriers. These characteristics make them highly appealing for development as cancer immunotherapeutics. Both natively secreted and engineered bEVs are now being investigated for their application as immunotherapeutics, vaccines, drug delivery vehicles, and combinations of the above, with promising early results. This suggests that both the intrinsic immunomodulatory properties of bEVs and their ability to be modified could be harnessed for the development of next-generation microbe-inspired therapies. Nonetheless, there remain major outstanding questions regarding how the observed preclinical effectiveness will translate from murine models to primates, and humans in particular. Moreover, research into the pharmacology, toxicology, and mass manufacturing of this potential novel therapeutic platform is still at early stages. In this review, we highlight the breadth of bEV interactions with host cells, focusing on immunologic effects as the main mechanism of action of bEVs currently in preclinical development. We review the literature on ongoing efforts to develop natively secreted and engineered bEVs from a variety of bacterial species for cancer therapy and finally discuss efforts to overcome outstanding challenges that remain for clinical translation.
越来越多的研究将人类微生物组的组成与疾病状态及治疗反应联系起来，尤其是在癌症背景下。这引发了人们对开发微生物及微生物产品作为癌症免疫疗法的浓厚兴趣，这类疗法可模拟或重现宿主 - 微生物相互作用的有益效果。细菌细胞外囊泡（bEVs）是几乎所有细菌物种分泌的纳米级膜结合颗粒，包含产生细胞的多种生物活性物质。它们在促进同种细胞、不同微生物物种的细胞之间，甚至在定植（微生物组）和感染背景下与多细胞宿主生物之间的相互作用中发挥着重要作用。在感染背景下，bEVs与免疫系统的相互作用已得到广泛研究，表明bEVs的作用在很大程度上取决于产生它们的物种。因此，它们不仅提供功能多样性，而且是非复制性的，具有内在的细胞靶向特性，并有可能克服天然屏障。这些特性使其作为癌症免疫疗法极具开发潜力。目前，天然分泌的和经过工程改造的bEVs都在作为免疫疗法、疫苗、药物递送载体以及上述多种用途的组合进行研究，初步结果很有前景。这表明bEVs的内在免疫调节特性及其可修饰能力都可用于开发下一代受微生物启发的疗法。尽管如此，关于如何将观察到的临床前有效性从鼠模型转化到灵长类动物，尤其是人类，仍然存在重大悬而未决的问题。此外，对这个潜在的新型治疗平台的药理学、毒理学和大规模生产的研究仍处于早期阶段。在这篇综述中，我们重点介绍bEVs与宿主细胞相互作用的广度，将免疫效应作为目前临床前开发中bEVs的主要作用机制进行阐述。我们回顾了关于利用多种细菌物种开发天然分泌的和经过工程改造的bEVs用于癌症治疗的文献，并最终讨论了为克服临床转化中仍然存在的突出挑战所做的努力。
