期刊
CHEMICAL ENGINEERING JOURNAL
卷 421, 期 -, 页码 -出版社
ELSEVIER SCIENCE SA
DOI: 10.1016/j.cej.2021.129774
关键词
Exosome; siRNA; Combination immunotherapy; Fibrinogen-like protein 1; Transforming growth factor-beta 1
资金
- National Key Technologies Research and Development Plan [SQ2019YFE012044, 2016YFE0119200]
- basic research cooperation project - Natural Science Foundation of Beijing [J200018]
- basic research cooperation project - Natural Science Foundation of Tianjin [20JCZXJC00070]
- Young Elite Scientists Sponsorship Program by Tianjin [TJSQNTJ201714]
This study introduced a combination therapeutic strategy for colorectal cancer by targeting the immune checkpoint LAG-3 ligand FGL1 and the immunosuppressive cytokine TGF-beta 1 simultaneously. The constructed cRGD-Exo/siMix exhibited significant anti-tumor effects by reshaping the tumor microenvironment and boosting anti-tumor immunity, providing a new approach for siRNA delivery in combined cancer immunotherapy.
Immune checkpoint therapy encounters significant challenges in clinic, including low response rate, acquired resistance and immune-related adverse events. Combination immunotherapy targeting multiple independent but complementary pathways in immune evasion has the potential to enhance therapeutic efficacy. Herein, a combination therapeutic strategy that dually inhibiting FGL1, a recently discovered main ligand for immune checkpoint LAG-3, and TGF-beta 1, an immunosuppressive cytokine, is firstly reported for colorectal cancer immunotherapy by blocking immune checkpoint and modulating tumor microenvironment simultaneously. We established a cRGD-modified exosome with high siFGL1 and siTGF-beta 1 loading efficiency (cRGD-Exo/siMix) to realize the co-silence of FGL1 and TGF-131. The constructed cRGD-Exo/siMix showed a significant anti-tumor effect both in vitro and in vivo. Analysis of the tumor immune microenvironment demonstrated an increased number of tumor infiltration CD8(+) T cells while a decreased number of immunosuppressive cells, implying that this therapeutic approach boosted anti-tumor immunity by reshaping the tumor microenvironment. This work provides a new strategy for siRNA delivery and its applications in combined cancer immunotherapy.
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