Ma Nana, Chen Zhiqiang, Liu Guangna, Yue Yale, Li Yao, Cheng Keman, Ma Xiaotu, Feng Qingqing, Liang Jie, Zhang Tianjiao, Gao Xiaoyu, Wang Xinwei, Guo Xinjing, Zhu Fei, Nie Guangjun, Zhao Xiao
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, No. 11 Zhongguancun Beiyitiao, Beijing 100190, China.
Institute of Smart Biomedical Materials, School of Materials Science and Engineering, Zhejiang Sci-Tech University, Hangzhou 310018, China.
ACS Nano. 2023 Jan 10;17(1):437-452. doi: 10.1021/acsnano.2c08880. Epub 2022 Dec 19.
In tumor nanovaccines, nanocarriers enhance the delivery of tumor antigens to antigen-presenting cells (APCs), thereby ensuring the robust activation of tumor antigen-specific effector T-cells to kill tumor cells. Through employment of their high immunogenicity and nanosize, we have developed a "Plug-and-Display" delivery platform on the basis of bacterial outer membrane vesicles (OMVs) for tumor nanovaccines (NanoVac), which can rapidly display different tumor antigens and efficiently eliminate lung metastases of melanoma. In this study, we first upgraded the NanoVac to increase their antigen display efficiency. However, we found that the presence of a subcutaneous xenograft seriously hampered the efficiency of NanoVac to eliminate lung metastases, with the subcutaneous xenograft mimicking the primary tumor burden in clinical practice. The primary tumor secreted significant amounts of granulocyte colony-stimulating factor (G-CSF) and altered the epigenetic features of granulocyte monocyte precursor cells (GMPs) in the bone marrow, thus disrupting systemic immunity, particularly the function of APCs, and ultimately resulting in NanoVac failure to affect metastases. These changes in the systemic immune macroenvironment were plastic, and debulking surgery of primary tumor resection reversed the dysfunction of APCs and failure of NanoVac. These results demonstrate that, in addition to the formulation design of the tumor nanovaccines themselves, the systemic immune macroenvironment incapacitated by tumor development is another key factor that cannot be ignored to affect the efficiency of tumor nanovaccines, and the combination of primary tumor resection with NanoVac is a promising radical treatment for widely metastatic tumors.
在肿瘤纳米疫苗中，纳米载体可增强肿瘤抗原向抗原呈递细胞（APC）的递送，从而确保强力激活肿瘤抗原特异性效应T细胞以杀伤肿瘤细胞。通过利用其高免疫原性和纳米尺寸，我们基于细菌外膜囊泡（OMV）开发了一种用于肿瘤纳米疫苗（NanoVac）的“即插即显”递送平台，该平台可快速展示不同的肿瘤抗原并有效消除黑色素瘤的肺转移灶。在本研究中，我们首先对NanoVac进行了升级以提高其抗原展示效率。然而，我们发现皮下异种移植物的存在严重阻碍了NanoVac消除肺转移灶的效率，皮下异种移植物模拟了临床实践中的原发性肿瘤负荷。原发性肿瘤分泌大量粒细胞集落刺激因子（G-CSF）并改变了骨髓中粒细胞单核细胞前体细胞（GMP）的表观遗传特征，从而破坏全身免疫，尤其是APC的功能，最终导致NanoVac无法影响转移灶。全身免疫宏观环境中的这些变化具有可塑性，原发性肿瘤切除的减瘤手术可逆转APC的功能障碍和NanoVac的失效。这些结果表明，除了肿瘤纳米疫苗本身的制剂设计外，肿瘤发展导致的全身免疫宏观环境丧失是影响肿瘤纳米疫苗效率的另一个不可忽视的关键因素，原发性肿瘤切除与NanoVac联合是广泛转移性肿瘤有前景的根治性治疗方法。
