Oncolytic Viral Therapy Mediates its Effectiveness by Inducing and Enhancing CD4 cytotoxic T-cells

Abstract

Abstract Malignant glioma remains a fatal disease with a dismal survival rate. To address this urgent medical need, we pioneered the concept of engineered oncolytic viruses for cancer. Using the herpes simplex virus (HSV)-1 as an experimental virus, our published Phase I trials have demonstrated the safety and efficacy of such oHSV-based therapy for treating brain tumor patients. In searching for biomarkers for better responses to this therapy, our preclinical studies using intracranial glioma models and an oHSV secreting murine IL-12 (M002) revealed that a subset of CD4+ T-cells expressing the cytolytic signatures, including granzyme B, were increased in M002-treated mice compared to vehicle-treated controls. Correspondingly, CD4+ T-cells isolated from brain tumors of M002-treated mice killed tumor cells better than cells isolated from control tumors. However, the factors and temporal requirements that direct the development of this CD4 cytotoxic T-cell (CTL) subset are not fully understood. To address this question, we performed single-cell RNA sequencing analysis of CD4+ T-cells isolated from brain tumors of M002-treated and control mice. The results revealed a complex change of the CD4+ T-cell compartment with CD4 CTLs being induced from two different precursors. The first CTL subset was derived from T helper-1 (Th1) cells and retained Th1 gene signatures while expressing high levels of CTL associated molecules. The second CTL subset was a reprogrammed regulatory T-cell population capable of producing high levels of cytokines and granzymes. Both CD4 CTL subsets were more prominent in M002-treated mice, suggesting that M002 therapy could induce CD4 CTLs with specialized functionality, which may account for its improved outcome. Supported by grants from DoD W81XH-18-1-0315 and UAB Start up Funds