Background
Malignant glioma, an aggressive type of brain tumor, remains an intractable problem with uniformly fatal outcomes in patients. We engineered herpes simplex virus (HSV)-1 and developed oncolytic HSV (oHSV) to treat brain tumors, given its capacity to selectively kill tumor cells while sparing normal cells, and to boost anti-tumor immunity. Both of our phase I trial and preclinical studies have demonstrated the safety and efficacy of this oHSV-based therapy. However, the nature of anti-tumor immune responses to such therapy remains largely unclear.
Methods
An oHSV expressing murine IL-12 (M002) and vehicle control were used to treat immunocompetent mice bearing intracranial glioma. The in vitro cell culture assays, in vivo adoptive transfer approaches and single-cell RNA sequencing coupled with T-cell receptor (TCR) repertoire analysis of intratumoral CD4+ T-cells were performed.
Results
We revealed that M002 treatment preferentially induced unique CD4+ T-cell populations in the tumor that were distinct from conventional T helper subsets and displayed less exhausted phenotype but increased effector activity. CD4+ T-cells isolated from M002-treated tumors prolonged mice survival and had better tumor-killing ability than CD4+ T-cells from vehicle-treated control tumors in an MHCII-dependent manner. Notably, M002 treatment reduced the CD4+ T-cell clonal diversity but expanded certain clones.
Conclusions
These results suggest that the capacity of oncolytic virotherapy to reshape the CD4+ T-cell repertoire and to enhance their anti-tumor functionality contributes to its improved efficacy. This study has provided insights into the immune-based mechanistic actions of oHSV therapy and has suggested the strategies for the development of better treatments for brain tumor patients.
Acknowledgements
This study was supported by DoD W81XH-18–1-0315 and the University of Alabama at Birmingham Faculty Start-up Funds.
Ethics Approval
All animal experiments were performed in compliance with federal laws and institutional guidelines as approved by the UAB IACUC.