IL-12 encapsulated and myeloid-targeted exosome-liposome hybrid system for reprogramming the GBM immunosuppressive microenvironment

• Applicant: Ommolbanin Asadpour, Ph.D., from 2/2024 until 1/2026
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 544660729

The last decade of research and clinical investigation of cancer immunotherapies has demonstrated curative efficacy, but only in a small proportion of patients. Expanding the use of promising immunotherapies to the vast majority of patients depends in part on appropriate modulation of the immune tumor microenvironment (TME). The nature of the stromal cells embedded in the context of the TME varies widely from tumor to tumor and is dynamically affected by therapy. Although extensive immunomodulatory therapies are used to improve treatment, effective treatment to overcome immunosuppression of the TME in adult brain tumors such as glioblastoma (GBM) remains elusive, which is a critical barrier to therapeutic efficacy. The TME of GBM is a heterogeneous, dynamic milieu that promotes immunosuppression through a variety of strategies, including infiltration of immunosuppressive myeloid cells (macrophages and myeloid-derived suppressor cells). Overexpression of PDL-1 on myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), as well as colony-stimulating factor receptor (CSF1-R), promotes T cells exhaustion, leading to a decrease in the number of CD8+ cytotoxic T cells in the tumor. On the other hand, secretion of potent cytokines such as IL-12 by TAM-1, stimulates the conversion of anergic T cells into activated cells and increases the infiltration of T cells into the tumor. another obstacle in combating this aggressive tumor is the blood-brain barrier (BBB), which prevents the effective delivery of more than 98% of therapeutic agents to the GBM. Thus, this interplay may contribute significantly to the design of immunosuppressive TME in the brain.

• DFG Programme: WBP Position