Zika virus-based immunotherapy enhances long-term survival of rodents with brain tumors through upregulation of memory T-cells.

Andrew T Crane ,Mark R Schleiss,Will Swanson,Maple Shiao,Winston Guo,Hui Xie,Nikolas G Toman,Christopher J Sipe,Matthew R Chrostek,Craig J Bierle,Shivanshi Vaid,Walter C Low,Venkatramana D Krishna,Wei Lu ,Maxim C.-J Cheeran ,Sarah K Tran ,Joseph Voth ,Clairice Pearce ,Andrew Grande

doi:10.1371/journal.pone.0232858

Abstract

Zika virus (ZIKV) exhibits a tropism for brain tumor cells and has been used as an oncolytic virus to target brain tumors in mice with modest effects on extending median survival. Recent studies have highlighted the potential for combining virotherapy and immunotherapy to target cancer. We postulated that ZIKV could be used as an adjuvant to enhance the long-term survival of mice with malignant glioblastoma and generate memory T-cells capable of providing long-term immunity against cancer remission. To test this hypothesis mice bearing malignant intracranial GL261 tumors were subcutaneously vaccinated with irradiated GL261 cells previously infected with the ZIKV. Mice also received intracranial injections of live ZIKV, irradiation attenuated ZIKV, or irradiated GL261 cells previously infected with ZIKV. Long-term survivors were rechallenged with a second intracranial tumor to examine their immune response and look for the establishment of protective memory T-cells. Mice with subcutaneous vaccination plus intracranial irradiation attenuated ZIKV or intracranial irradiated GL261 cells previously infected with ZIKV exhibited the greatest extensions to overall survival. Flow cytometry analysis of immune cells within the brains of long-term surviving mice after tumor rechallenge revealed an increase in the number of T-cells, including CD4+ and tissue-resident effector/ effector memory CD4+ T-cells, in comparison to long-term survivors that were mock-rechallenged, and in comparison to naïve untreated mice challenged with intracranial gliomas. These results suggest that ZIKV can serve as an adjuvant to subcutaneous tumor vaccines that enhance long-term survival and generate protective tissue-resident memory CD4+ T-cells.

Highlights

Glioblastoma multiforme (GBM) is a highly aggressive malignant brain tumor whose treatment options currently offer little chance of long-term survival or cure
Lysates from GL261 and BV2 cell lines were collected at 1-days post-infection (DPI) and 3-DPI for qRT-PCR analysis of transcripts related to endosomal (TLR3) and cytoplasmic (MDA5 and RIG-I) viral RNA detection [15]
Relative to mock-infected cells, an increase in expression of TLR3 was observed at 1-DPI and 3-DPI, and increases in expression of MDA5 and RIG-I were observed at 3-DPI, which was not observed in BV2 cells (Fig 1E)

Summary

Introduction

Glioblastoma multiforme (GBM) is a highly aggressive malignant brain tumor whose treatment options currently offer little chance of long-term survival or cure. Patients with GBM typically undergo surgical resection followed by treatment with chemotherapy and temozolomide [1], with a median overall survival (OS) of only 16 months [2]. Oncolytic viruses offer a promising avenue for treating GBM. Viral tropism can be exploited to target tumor cells with greater efficiency and fewer side effects when compared to treatment with chemotherapy and temozolomide [3]. Viruses are thought to induce an anti-tumor immune response through the direct lysis of infected cells and release of tumor-associated antigens, as well as the activation of antiviral pathways, creating an adaptive immune response against tumor and virus [5]

Methods

Results

Conclusion