Dose-related immunomodulatory effects of recombinant TRAIL in the tumor immune microenvironment

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dc.contributor.authorWang, Xupu
dc.contributor.authorWang, Lizheng
dc.contributor.authorLiu, Wenmo
dc.contributor.authorLiu, Xinyao
dc.contributor.authorJia, Xinyuan
dc.contributor.authorFeng, Xinyao
dc.contributor.authorLi, Fangshen
dc.contributor.authorZhu, Rui
dc.contributor.authorYu, Jiahao
dc.contributor.authorZhang, Haihong
dc.contributor.authorWu, Hui
dc.contributor.authorWu, Jiaxin
dc.contributor.authorWang, Chu
dc.contributor.authorYu, Bin
dc.contributor.authorYu, Xianghui
dc.date.accessioned2023-08-27T00:02:42Z
dc.date.available2023-08-27T00:02:42Z
dc.date.issued2023-08-22
dc.date.updated2023-08-27T00:02:42Z
dc.description.abstractAbstract 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
dc.identifier.citationJournal of Experimental & Clinical Cancer Research. 2023 Aug 22;42(1):216
dc.identifier.urihttps://doi.org/10.1186/s13046-023-02795-x
dc.identifier.urihttps://hdl.handle.net/1880/116907
dc.identifier.urihttps://dx.doi.org/10.11575/PRISM/41749
dc.language.rfc3066en
dc.rights.holderItalian National Cancer Institute ‘Regina Elena’
dc.titleDose-related immunomodulatory effects of recombinant TRAIL in the tumor immune microenvironment
dc.typeJournal Article
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