期刊
NANO LETTERS
卷 22, 期 5, 页码 2048-2058出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.nanolett.1c04977
关键词
Neoantigen; stimulator of interferon genes (STING) agonist; toll-like receptor 9 agonist; TIM-3 antibody; silk-hydrogel
类别
资金
- National Natural Science Foundation of China [62175031]
- Natural Science Foundation of Fujian Province of China [2020J02010, 2020J011154]
- Scientific Foundation of Fuzhou Municipal Health commission [2021-S-wp1]
- Young and Middle-aged Talent Training Project of Fujian Provincial Health Commission [2021GGB020]
This study combines various therapeutic approaches, such as liver cancer-specific neoantigen, immune agonists, and TIM-3 blockade, using a silk-hydrogel package to effectively treat and provide long-term immune protection against orthotopic hepatocellular carcinoma (HCC). The synergistic immunotherapy significantly reduces tumor growth, prevents metastasis, and establishes long-term memory against tumor rechallenge.
Herein, we integrate the Hepa1-6 liver cancer-specific neoantigen, toll-like receptor 9 agonist and stimulator of interferon genes agonist by silk-hydrogel package, and combine with TIM-3 blockade to elicit robust antitumor immunity for effectively suppressing orthotopic hepatocellular carcinoma (HCC) progression. Unlike intradermal injection of simple mixed components with short-term immune protection, the neoantigen immunotherapeutic-gels evoke long-term immune protection to achieve significant prophylactic and therapeutic activity against HCC through only one-shot administration without any side effects. Notably, the synergized immunotherapy by further combining NGC-gels with TIM-3 antibody significantly reduces regulatory T-cells and increases the IFN-gamma and IL-12p70 levels in tumor tissues for promoting the infiltration of IFN-gamma+CD8+T-cells and 41BB+CD8+T-cells to achieve complete remission (4/7) and prevent pulmonary metastasis in orthotopic HCC, and establish long-term memory against tumor rechallenge with remarkably longer survival time (180 days). Overall, this study provides an attractive and promising synergistic strategy for HCC immunotherapy with possible clinical translation prospects.
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