Gene engineered exosome reverses T cell exhaustion in cancer immunotherapy

• Published in: Bioactive materials Vol. 34; pp. 466 - 481
• Main Authors: Li, Peishan, Xie, Ying, Wang, Jinling, Bao, Chunjie, Duan, Jialun, Liu, Yixuan, Luo, Qian, Xu, Jiarui, Ren, Yuxin, Jiang, Min, Li, Jianwei, Guo, Haitao, Zhao, Huihui, Wang, Guiling, Liang, Yanqin, Lu, Wanliang
• Format: Journal Article
• Language: English
• Published: China Elsevier B.V 01.04.2024; KeAi Publishing; KeAi Communications Co., Ltd
• Subjects: Cancer immunotherapy; Gene engineered exosomes; Imiquimod; PD1/PDL1; T cell exhaustion; T cell exhaustion; Gene engineered exosomes; Cancer immunotherapy; PD1/PDL1; Imiquimod
• ISSN: 2452-199X; 2452-199X
• DOI: 10.1016/j.bioactmat.2024.01.008

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. Illustration for rational design of PD1 gene engineered exosomes.(A) Immune surveillance escape. Cancer cells resist to the host immune antitumor response via overexpressing programmed cell death ligand 1 (PDL1) that exhausts antigen-specific CD8+ T cells through binding with programmed cell death protein 1 (PD1) receptor. (B) Reversal of T cell exhaustion. The immune activation effect was achieved through antagonizing the PD1/PDL1 axis by PD1 gene engineered exosome (PD1-Imi Exo), and maturation of immature dendritic cells by immune adjuvant imiquimod released from PD1-Imi Exo. [Display omitted] •PD1 gene engineered exosome rationally designed by enveloping imiquimod (PD1-Imi Exo).•Imiquimod promoting maturation of dendritic cells and further activating T cells.•PD1-Imi Exo reversing T cell exhaustion and competitively blocking PD1/PDL1 axis.•PD1-Imi Exo boosting cancer immunotherapy and preventing metastasis after surgery.