利用LMP2-mRNA脂质纳米粒子逆转T细胞筋疲力竭，使EBV相关肿瘤对抗PD-1疗法敏感。
LMP2-mRNA lipid nanoparticle sensitizes EBV-related tumors to anti-PD-1 therapy by reversing T cell exhaustion.
发表日期：2023 Sep 08
作者：
Yu Xiang, Miaomiao Tian, Juan Huang, Yueyi Li, Guangqi Li, Xue Li, Zedong Jiang, Xiangrong Song, Xuelei Ma
来源：
JOURNAL OF NANOBIOTECHNOLOGY
摘要：
靶向EBV蛋白的mRNA疫苗是治疗与EBV相关肿瘤，如鼻咽癌（NPC）的一种有希望的方法。我们假设它可以使肿瘤对免疫检查点抑制剂更加敏感。我们开发了一种能够传递到肿瘤引流淋巴结的LMP2-mRNA脂质纳米颗粒（C2@mLMP2）。C2@mLMP2表现出高转染效率和溶酶体逃逸能力，并在小鼠模型的脾脏中诱导了CD8+ 中央记忆T细胞和CD8+ 有效记忆T细胞的比例增加。在带肿瘤小鼠中观察到C2@mLMP2与αPD-1的强协同抗肿瘤效应。机制被确定与肿瘤微环境中CD8+ T细胞耗竭有关。病理分析进一步证明了疫苗和联合治疗的安全性。这是首个证明EBV-mRNA疫苗和PD-1抑制剂在EBV相关肿瘤中协同作用的研究。本研究为进一步的临床试验提供了理论依据，可能扩大免疫治疗在NPC中的应用场景和功效。© 2023 BioMed Central Ltd., part of Springer Nature.
Targeting EBV-proteins with mRNA vaccines is a promising way to treat EBV-related tumors like nasopharyngeal carcinoma (NPC). We assume that it may sensitize tumors to immune checkpoint inhibitors.We developed an LMP2-mRNA lipid nanoparticle (C2@mLMP2) that can be delivered to tumor-draining lymph nodes. C2@mLMP2 exhibited high transfection efficiency and lysosomal escape ability and induced an increased proportion of CD8 + central memory T cells and CD8 + effective memory T cells in the spleen of the mice model. A strong synergistic anti-tumor effect of C2@mLMP2 in combination with αPD-1 was observed in tumor-bearing mice. The mechanism was identified to be associated with a reverse of CD8 + T cell exhaustion in the tumor microenvironment. The pathological analysis further proved the safety of the vaccine and the combined therapy.This is the first study proving the synergistic effect of the EBV-mRNA vaccine and PD-1 inhibitors for EBV-related tumors. This study provides theoretical evidence for further clinical trials that may expand the application scenario and efficacy of immunotherapy in NPC.© 2023. BioMed Central Ltd., part of Springer Nature.