Oncolytic HSV Therapy Modulates Vesicular Trafficking Inducing Cisplatin Sensitivity and Antitumor Immunity

Here we investigated the impact of oncolytic herpes simplex virus (HSV) treatment on cisplatin sensitivity of platinum-resistant ovarian cancer, and the impact of the combination on immunotherapy. Therapeutic efficacy of the combination was assessed in platinum-resistant human and murine ovarian can...

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Bibliographic Details
Published in:Clinical cancer research 2021-01, Vol.27 (2), p.542-553
Main Authors: Hong, Bangxing, Chapa, Valerie, Saini, Uksha, Modgil, Puneet, Cohn, David E, He, Guangan, Siddik, Zahid H, Sood, Anil K, Yan, Yuanqing, Selvendiran, Karuppaiyah, Pei, Guangsheng, Zhao, Zhongming, Yoo, Ji Young, Kaur, Balveen
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - therapeutic use
Cell Line, Tumor
Cells, Cultured
Cisplatin - therapeutic use
Combined Modality Therapy
Disease Models, Animal
DNA Adducts - genetics
DNA Adducts - immunology
Female
Herpesvirus 1, Human - physiology
Humans
Immunotherapy - methods
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Oncolytic Virotherapy - methods
Ovarian Neoplasms - genetics
Ovarian Neoplasms - therapy
Ovarian Neoplasms - virology
Signal Transduction - genetics
Signal Transduction - immunology
Treatment Outcome
Xenograft Model Antitumor Assays - methods
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Summary:Here we investigated the impact of oncolytic herpes simplex virus (HSV) treatment on cisplatin sensitivity of platinum-resistant ovarian cancer, and the impact of the combination on immunotherapy. Therapeutic efficacy of the combination was assessed in platinum-resistant human and murine ovarian cancer peritoneal metastatic mouse models ( = 9-10/group). RNA sequencing along with flow cytometry of splenocytes from treated mice was employed to examine the effect of antitumor immune response ( = 3/group). Anti-PD-1 antibody was performed to evaluate impact on checkpoint inhibition . 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 cisplatin 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 antitumor immunity and efficacy. In mice bearing platinum-resistant ovarian cancer, we also observed a feedback induction of PD-L1 on tumor cells, which sensitized combination-treated mice to anti-PD-1 immune checkpoint therapy. 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 antitumor immunity. The combination therapy also created an environment that sensitized tumors to immune checkpoint therapy.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.ccr-20-2210