Advisory Committee Chair
Jianmei Leavenworth
Document Type
Dissertation
Date of Award
2024
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Glioblastoma multiforme (GBM), the most commonly occurring type of malignant glioma, currently has no cure, and all cases remain universally fatal. Oncolytic herpes simplex virus (oHSV) therapy has shown promise in the treatment of GBM in both clinical and preclinical studies by boosting anti-tumor immune responses. However, the composition and quality of the immune response induced by oHSV therapy are not fully understood. Using murine intracranial GBM models along with our engineered oHSV expressing murine interleukin (IL)-12 (M002), we observed that M002 treatment induced MHCII upregulation on tumor cells, consistent with our clinical trial results (NCT00028158), and expanded intratumoral CD4 T cells with enhanced functionality and a significant change to the available T cell receptor (TCR) repertoire. Depletion and adoptive transfer of M002-programed CD4 T cells further illustrated that the therapy was mediating a significant portion of its efficacy in an CD4 T cell dependent manner. Furthermore, M002 therapy induced a novel Th1 like population (termed as cluster 1 cells), which expressed high levels of CD40lg and CXCR6 while lacking Lag-3, and comprised the most expanded clones, as revealed by single-cell RNA sequencing and TCR repertoire analysis. Mechanistically, M002 treatment induced an early upregulation of T-bet and activated non-canonical NF-kB pathways along with increased proinflammatory signals to promote the acquisition of the cluster 1 phenotype. Ablation of T-bet ablated all therapeutic benefit of M002 and prevented the formation of the cluster 1 phenotype. Although the early CD4 T-cell anti-tumor activity did not require Bcl6 expression, a Bcl6-depedent memory-like population was generated at the late-stage post-M002 treatment to mediate durable tumor control, coinciding with the acquisition of a tissue resident memory (Trm) phenotype by cluster 1 cells. These findings revealed an essential role of CD4 T cells in the direct control of GBM and a novel CD4 T cell population with Trm properties, suggesting potential strategies for future therapies of GBM.
Recommended Citation
Grimes, Jeffrey, "Oncolytic Viral Therapy Reshapes The Anti-Glioma Cd4 T Cell Response And Their Tcr Repertoire" (2024). All ETDs from UAB. 3850.
https://digitalcommons.library.uab.edu/etd-collection/3850