Outer Membrane Vesicle-Based Nanohybrids Target Tumor-Associated Macrophages to Enhance Trained Immunity-Related Vaccine-Generated Antitumor Activity,Advanced Materials

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Outer Membrane Vesicle-Based Nanohybrids Target Tumor-Associated Macrophages to Enhance Trained Immunity-Related Vaccine-Generated Antitumor Activity
Advanced Materials ( IF 27.4 ) Pub Date : 2023-08-29 , DOI: 10.1002/adma.202306158
Jie Liang _{1,

2} , Fei Zhu ₁ , Keman Cheng ₁ , Nana Ma ₁ , Xiaotu Ma ₁ , Qingqing Feng ₁ , Chen Xu ₁ , Xiaoyu Gao ₁ , Xinwei Wang ₁ , Jian Shi ₁ , Xiao Zhao _{1,

2} , Guangjun Nie _{1,

2}

Affiliation

Trained immunity refers to the innate immune system building memory-like features in response to subsequent infections and vaccinations. Compared with classical tumor vaccines, trained immunity-related vaccines (TIrV) are independent of tumor-specific antigens. Bacterial outer membrane vesicles (OMVs) contain an abundance of PAMPs and have the potential to act as TIrV-inducer, but face challenges in endotoxin tolerance, systemic delivery, long-term training, and trained tumor-associated macrophage (TAM)-mediated antitumor phagocytosis. Here, an OMV-based TIrV is developed, OMV nanohybrids (OMV-SIRPα@CaP/GM-CSF) for exerting vaccine-enhanced antitumor activity. In the bone marrow, GM-CSF-assisted OMVs train bone marrow progenitor cells and monocytes, which are inherited by TAMs. In tumor tissues, SIRPα-Fc-assisted OMVs trigger TAM-mediated phagocytosis. This TIrV can be identified by metabolic and epigenetic rewiring using transposase-accessible chromatin (ATAC) and transcriptome sequencing. Furthermore, it is found that the TIrV-mediated antitumor mechanism in the MC38 tumor model (TAM-hot and T cell-cold) is trained immunity and activated T cell response, whereas in the B16-F10 tumor model (T cell-hot and TAM-cold) is primarily mediated by trained immunity. This study not only develops and identifies OMV-based TIrV, but also investigates the trained immunity signatures and therapeutic mechanisms, providing a basis for further vaccination strategies.

中文翻译：

基于外膜囊泡的纳米杂交体靶向肿瘤相关巨噬细胞，以增强经过训练的免疫相关疫苗产生的抗肿瘤活性

训练有素的免疫是指先天免疫系统建立类似记忆的功能来应对随后的感染和疫苗接种。与经典肿瘤疫苗相比，经过训练的免疫相关疫苗（TIrV）不依赖于肿瘤特异性抗原。细菌外膜囊泡 (OMV) 含有丰富的 PAMP，有潜力充当 TIrV 诱导剂，但在内毒素耐受、全身递送、长期训练和经过训练的肿瘤相关巨噬细胞 (TAM) 介导的抗肿瘤方面面临挑战吞噬作用。在这里，开发了一种基于 OMV 的 TIrV，即 OMV 纳米杂交体 (OMV-SIRPα@CaP/GM-CSF)，用于发挥疫苗增强的抗肿瘤活性。在骨髓中，GM-CSF 辅助的 OMV 训练骨髓祖细胞和单核细胞，这些细胞由 TAM 遗传。在肿瘤组织中，SIRPα-Fc 辅助的 OMV 触发 TAM 介导的吞噬作用。该 TIrV 可以通过使用转座酶可及染色质 (ATAC) 和转录组测序进行代谢和表观遗传重连来识别。此外，发现 MC38 肿瘤模型（TAM 热和 T 细胞冷）中 TIrV 介导的抗肿瘤机制是训练免疫和激活 T 细胞反应，而在 B16-F10 肿瘤模型（T 细胞热和 T 细胞冷）中，TIrV 介导的抗肿瘤机制是训练免疫和激活 T 细胞反应。 TAM-感冒）主要由训练有素的免疫力介导。这项研究不仅开发和鉴定了基于OMV的TIrV，而且还研究了经过训练的免疫特征和治疗机制，为进一步的疫苗接种策略提供了基础。

更新日期：2023-08-29

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