Gene engineered exosome reverses T cell exhaustion in cancer immunotherapy  

作　　者：Peishan Li Ying Xie Jinling Wang Chunjie Bao Jialun Duan Yixuan Liu Qian Luo Jiarui Xu Yuxin Ren Min Jiang Jianwei Li Haitao Guo Huihui Zhao Guiling Wang Yanqin Liang Wanliang Lu 

机构地区：[1]State Key Laboratory of Natural and Biomimetic Drugs,Beijing Key Laboratory of Molecular Pharmaceutics and Drug Delivery Systems,School of Pharmaceutical Sciences,Peking University,Beijing,100191,China [2]Modern Research Center for Traditional Chinese Medicine,Beijing Research Institute of Chinese Medicine,Beijing University of Chinese Medicine,Beijing,100029,China [3]Beijing Institute of Collaborative Innovation,Beijing,100044,China

出　　处：《Bioactive Materials》2024年第4期466-481,共16页生物活性材料（英文）

基　　金：supported by the National Natural Science Foundation of China(No.82173752 and No.81874303).

摘　　要：Cancer patients by immune checkpoint therapy have achieved long-term remission,with no recurrence of clinical symptoms of cancer for many years.Nevertheless,more than half of cancer patients are not responsive to this therapy due to immune exhaustion.Here,we report a novel gene engineered exosome which is rationally designed by engineering PD1 gene and simultaneously enveloping an immune adjuvant imiquimod(PD1-Imi Exo)for boosting response of cancer immune checkpoint blockage therapy.The results showed that PD1-Imi Exo had a vesicular round shape(approximately 139 nm),revealed a significant targeting and a strong binding effect with both cancer cell and dendritic cell,and demonstrated a remarkable therapeutic efficacy in the melanoma-bearing mice and in the breast cancer-bearing mice.The mechanism was associated with two facts that PD1-Imi Exo blocked the binding of CD8^(+)T cell with cancer cell,displaying a PD1/PDL1 immune checkpoint blockage effect,and that imiquimod released from PD1-Imi Exo promoted the maturation of immature dendritic cell,exhibiting a reversing effect on the immune exhaustion through activating and restoring function of CD8^(+)T cell.In conclusion,the gene engineered exosome could be used for reversing T cell exhaustion in cancer immunotherapy.This study also offers a promising new strategy for enhancing PD1/PDL1 therapeutic efficacy,preventing tumor recurrence or metastasis after surgery by rebuilding the patients’immunity,thus consolidating the overall prognosis.

关 键 词：Gene engineered exosomes T cell exhaustion PD1/PDL1 IMIQUIMOD Cancer immunotherapy 

分 类 号：R730.51[医药卫生—肿瘤] R318[医药卫生—临床医学]