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Dose-related immunomodulatory effects of recombinant TRAIL in the tumor immune microenvironment
Xupu Wang1, Lizheng Wang1,2, Wenmo Liu1
1National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, China.
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.
Insights
Recombinant tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has dose-dependent effects on the tumor microenvironment. Optimal doses activate anti-tumor immunity, while higher doses promote tumor growth, suggesting tailored TRAIL strategies are crucial for cancer therapy.
Area of Science:
- Immunology
- Cancer Biology
- Drug Development
Background:
- Recombinant tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) influences the cancer immune microenvironment, but its mechanisms are unclear.
- Understanding TRAIL's immunomodulatory effects is vital for developing novel cancer therapies.
Purpose of the Study:
- To investigate the immunomodulatory effects and mechanisms of recombinant TRAIL in the tumor microenvironment (TME).
- To explore potential therapeutic strategies combining TRAIL with other agents.
Main Methods:
- Immunocompetent mice with tumors were treated with varying doses of recombinant TRAIL.
- Immunological detection and mechanistic investigations were performed using flow cytometry and single-cell sequencing.
- A humanized immune system mouse model was utilized to verify findings with human TRAIL.
Main Results:
- Recombinant soluble mouse TRAIL (smTRAIL) exhibited dose-dependent immunomodulatory effects.
- Optimal smTRAIL doses (2 mg/kg) activated innate immune cells and CD8+ T cells.
- Higher smTRAIL doses (8 mg/kg) promoted a tumor-promoting microenvironment, including M2-like macrophages and IL-10 production, suppressing NK and CD8+ T cells.
- Combinational administration of recombinant soluble human TRAIL (shTRAIL) and trabectedin remodeled the TME, enhanced antitumor immunity, and improved therapeutic effects in a humanized model.
Conclusions:
- Recombinant TRAIL plays a significant immunomodulatory role in the TME.
- Tailored TRAIL administration and combination therapies show promise for clinical cancer treatment.
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