PURPOSE : Here we investigated the impact of oncolytic HSV (oHSV) treatment on cisplatin sensitivity of platin resistant ovarian cancer (OC), and the impact of the combination on immunotherapy.

EXPERIMENTAL DESIGN : Therapeutic efficacy of the combination was assessed in platin resistant human and murine OC peritoneal metastatic mouse models (n=9-10/group). RNA sequencing along with flow cytometry of splenocytes from treated mice was employed to examine the effect of anti-tumor immune response (n=3/group). Anti-PD-1 antibody was performed to evaluate impact on checkpoint inhibition in vivo.

RESULTS : Gene ontology pathway analysis uncovered disruption of cellular extracellular vesicle (EV) related pathways in infected cells (FDR=2.97E-57). Mechanistically we identified reduced expression of transporters expressed on EV implicated in CP efflux. The increased cisplatin retention led to increased cisplatin-DNA adducts, which resulted in micronuclei and the subsequent activation of cGAS-STING pathway with a significant activation of innate immune cells and translated to an increase in anti-tumor immunity and efficacy. In mice bearing platin resistant OC we also observed a feed-back induction of PD-L1 on tumor cells, which sensitized combination treated mice to anti-PD-1 immune checkpoint therapy.

CONCLUSION : To our knowledge this is the first report to show HSV induced cisplatin retention in infected cells. The consequential increased damaged DNA was then expelled from cells as micronuclei which resulted in induction of inflammatory responses and education of anti-tumor immunity. The combination therapy also created an environment that sensitized tumors to immune checkpoint therapy.