Antitumor Immunity Mediated by Engineered Stem Cells Exploiting TRAIL-Induced Cell Death and FLT3L Immunomodulation

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Glioblastoma (GBM) is a highly malignant brain tumor.
• Death receptor (DR)-targeted therapies are promising for GBM.
• The impact of DR-mediated cell death on the tumor immune microenvironment (TIME) is unclear.

Purpose of the Study:

• To explore the immunomodulatory role of secretable human tumor necrosis factor (TNF)-related apoptosis-inducing ligand (S-TRAIL).
• To evaluate the therapeutic potential of allogeneic stem cells (SCs) delivering S-TRAIL and FMS-like tyrosine kinase 3 ligand (FLT3L).

Main Methods:

• Created syngeneic mouse GBM models (immune-active and -suppressive) with chimeric DR5.
• Developed therapeutic SCs releasing FLT3L and S-TRAIL.
• Assessed efficacy of encapsulated SC-TRAIL/FLT3L in syngeneic and humanized GBM resection models.

Main Results:

• S-TRAIL induced GBM cell apoptosis and dendritic cell (DC) infiltration and maturation in the TIME.
• Transplantation of encapsulated SCs post-resection improved survival and upregulated cDC1 and CD8+ T cells.
• Encapsulated clinical-grade SCs significantly reduced tumor volumes in humanized mice.

Conclusions:

• S-TRAIL-mediated cell death plays an immunological role in the TIME.
• Encapsulated cell-based therapy can eliminate residual GBM cells.
• This approach can induce long-term anti-tumor immunity.