Abstract
Immunotherapeutic approaches to treating glioblastoma (GBM) such as immune checkpoint blockade or dendritic cell vaccines have so far failed in recent clinical trials, despite showing some success in other cancer types. This failure has been attributed partly to the profound immunosuppressive tumor micro-environment (TME), characterized by dysfunctional cytotoxic T cell response and significant infiltration of regulatory lymphocytes and suppressive myeloid cells. We hypothesize that an oncolytic HSV1 (oHSV) which has a direct tumor cytotoxicity and potent
in situ
immunostimulation may reverse these immune dysfunction state and therefore improve tumor regression. Using several unique reagents, we found that oHSV treatment led to substantial reduction in tumor volume compared to PBS-control mice (oHSV- 9/11 vs PBS- 0/5; p= 0.0022), translating to longer term survival. Interestingly, oHSV led to improved tumor-specific T cells response with an expansion of tumor antigen-specific CD8+ T cells within the TME on both day 3 (oHSV- 4% vs PBS- 2%; p = 0.02) and day 7 (oHSV- 6.51% vs PBS- 1.33%; p = 0.04) following treatment, and a higher expression of IFNγ by CD8+ T cells compared to control (oHSV- 0.21% vs PBS- 5.60%; p = 0.04), suggesting an improved tumor-specific T cell functionality. Importantly, we found that this expansion of tumor-antigen specific CD8+ T cells inversely correlated with the tumor volume (R
2
= 0.41, p= 0.008). oHSV also led to a decrease in microglia and suppressive myeloid cell population which correlate negatively with the number of infiltating tumor-specific CD8+ T cells, suggesting they may play a role in modulating oHSV-mediated expansion of tumor specific T cells. Overall, using these novel tools, we demonstrate for the first time, that oHSV, in addition to its direct cytotoxic effect, play an important immunostimulating role through its modulation of tumor-specific T cells and myeloid cell population within the GBM tumor micro-environment.