Author:
Wang Xupu,Wang Lizheng,Liu Wenmo,Liu Xinyao,Jia Xinyuan,Feng Xinyao,Li Fangshen,Zhu Rui,Yu Jiahao,Zhang Haihong,Wu Hui,Wu Jiaxin,Wang Chu,Yu Bin,Yu Xianghui
Abstract
Abstract
Background
In addition to specifically inducing tumor cell apoptosis, recombinant tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has also been reported to influence the cancer immune microenvironment; however, its underlying effects and mechanisms remain unclear. Investigating the immunomodulatory effects and mechanisms of recombinant TRAIL in the tumor microenvironment (TME) may provide an important perspective and facilitate the exploration of novel TRAIL strategies for tumor therapy.
Methods
Immunocompetent mice with different tumors were treated with three doses of recombinant TRAIL, and then the tumors were collected for immunological detection and mechanistic investigation. Methodological approaches include flow cytometry analysis and single-cell sequencing.
Results
In an immunocompetent mouse model, recombinant soluble mouse TRAIL (smTRAIL) had dose-related immunomodulatory effects. The optimal dose of smTRAIL (2 mg/kg) activated innate immune cells and CD8+ T cells, whereas higher doses of smTRAIL (8 mg/kg) promoted the formation of a tumor-promoting immune microenvironment to counteract the apoptotic effects on tumor cells. The higher doses of smTRAIL treatment promoted M2-like macrophage recruitment and polarization and increased the production of protumor inflammatory cytokines, such as IL-10, which deepened the suppression of natural killer (NK) cells and CD8+ T cells in the tumor microenvironment. By constructing an HU-HSC-NPG.GM3 humanized immune system mouse model, we further verified the immunomodulatory effects induced by recombinant soluble human TRAIL (shTRAIL) and found that combinational administration of shTRAIL and trabectedin, a macrophage-targeting drug, could remodel the tumor immune microenvironment, further enhance antitumor immunity, and strikingly improve antitumor effects.
Conclusion
Our results highlight the immunomodulatory role of recombinant TRAIL and suggest promising therapeutic strategies for clinical application.
Graphical Abstract
Funder
National Natural Science Foundation of China
Jilin University Science and Technology Innovative Research Team
the “Medicine + X” Interdisciplinary Innovation Team of Norman Bethune Health Science Center of Jilin University
Publisher
Springer Science and Business Media LLC
Cited by
2 articles.
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