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

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

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6 Scopus citations


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.

Original languageEnglish (US)
Article numbere0232858
JournalPloS one
Issue number10
StatePublished - Oct 2020

Bibliographical note

Publisher Copyright:
Copyright: © 2020 Crane et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


  • Adjuvants, Immunologic
  • Animals
  • Brain Neoplasms/immunology
  • CD4-Positive T-Lymphocytes/immunology
  • Cancer Vaccines
  • Glioblastoma/immunology
  • Immunologic Memory
  • Immunotherapy
  • Mice
  • Mice, Inbred C57BL
  • Oncolytic Virotherapy
  • T-Lymphocytes/immunology
  • Zika Virus/immunology

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article
  • Research Support, N.I.H., Extramural


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