Kim Woo Sik, Choi DaeSeong, Park Ji Min, Song Ha-Yeon, Seo Ho Seong, Lee Dong-Eun, Byun Eui-Baek
Research Division for Radiation Science, Korea Atomic Energy Research Institute, Jeongeup 56212, Korea.
General Toxicology Research Center, Korea Institute of Toxicology, Jeongup 56212, Korea.
Vaccines (Basel). 2020 Nov 19;8(4):699. doi: 10.3390/vaccines8040699.
Cancer cells can secrete exosomes under various stressful conditions, whose functions are involved in the delivery of various biologically active materials into host cells and/or modulation of host immune responses. Therefore, an improved understanding of the immunological interventions that stress-induced tumor exosomes have may provide novel therapeutic approaches and more effective vaccine designs. Here, we confirmed the phenotypical and functional alterations of dendritic cells (DCs), which act as a bridge between the innate and adaptive arms of immunity, following non-irradiated (N-exo) and gamma-irradiated melanoma cancer cell-derived exosome (G-exo) stimulation, and evaluated the N-exo- and G-exo-stimulated DCs as therapeutic cancer vaccine candidates. We demonstrated that G-exo-stimulated DCs result in DC maturation by the upregulation of surface molecule expression, pro-inflammatory cytokine release, and antigen-presenting ability, and the downregulation of endocytic capacity. In addition, these cells promoted T cell proliferation and the generation of T helper type 1 (Th1) and interferon (IFN)-γ-producing CD8 T cells. However, N-exo-stimulated DCs induced semi-mature phenotypes and functions, eventually inhibiting T cell proliferation, decreasing IFN-γ, and increasing IL-10-producing CD4 T cells. In addition, although N-exo and G-exo stimulations showed similar levels of antigen-specific IFN-γ production, which served as tumor antigen sources in melanoma-specific T cells, G-exo-stimulated DC vaccination conferred a stronger tumor growth inhibition than N-exo-stimulated DC vaccination; further, this was accompanied by a high frequency of tumor-specific, multifunctional effector T cells. These results suggest that gamma irradiation could provide important clues for designing and developing effective exosome vaccines that can induce strong immunogenicity, especially tumor-specific multifunctional T cell responses.
癌细胞可在各种应激条件下分泌外泌体，其功能涉及将各种生物活性物质递送至宿主细胞和/或调节宿主免疫反应。因此，深入了解应激诱导的肿瘤外泌体的免疫干预作用，可能会提供新的治疗方法和更有效的疫苗设计。在此，我们证实了作为免疫固有和适应性分支之间桥梁的树突状细胞（DCs）在未辐照（N-exo）和γ-辐照的黑色素瘤癌细胞衍生外泌体（G-exo）刺激后的表型和功能改变，并评估了N-exo和G-exo刺激的DCs作为治疗性癌症疫苗候选物的潜力。我们证明，G-exo刺激的DCs通过上调表面分子表达、促炎细胞因子释放和抗原呈递能力以及下调内吞能力，导致DC成熟。此外，这些细胞促进了T细胞增殖以及1型辅助性T细胞（Th1）和产生干扰素（IFN）-γ的CD8 T细胞的生成。然而，N-exo刺激的DCs诱导了半成熟的表型和功能，最终抑制了T细胞增殖，降低了IFN-γ水平，并增加了产生白细胞介素-10的CD4 T细胞。此外，尽管N-exo和G-exo刺激在黑色素瘤特异性T细胞中作为肿瘤抗原来源的抗原特异性IFN-γ产生水平相似，但G-exo刺激的DC疫苗接种比N-exo刺激的DC疫苗接种具有更强的肿瘤生长抑制作用；此外，这伴随着高频率的肿瘤特异性多功能效应T细胞。这些结果表明，γ辐照可为设计和开发能诱导强免疫原性，尤其是肿瘤特异性多功能T细胞反应的有效外泌体疫苗提供重要线索。
