Vesicular Stomatitis Virus Encoding a Destabilized Tumor Antigen Improves Activation of Anti-tumor T Cell Responses

Amanda L. Huff, Laura Evgin, Jill Thompson, Tim Kottke, Christopher B. Driscoll, Jason Tonne, Phonphimon Wongthida, Matthew Schuelke, Kevin G. Shim, Georges Mer, Marina Ramirez-Alvarado, Richard Vile

Research output: Contribution to journalArticlepeer-review

Abstract

Enhancing the immunogenicity of tumor-associated antigens would represent a major advance for anti-tumor vaccination strategies. Here, we investigated structure-directed antigen destabilization as a strategy to improve the degradation, immunogenic epitope presentation, and T cell activation against a vesicular stomatitis virus (VSV)-encoded tumor antigen. We used the crystal structure of the model antigen ovalbumin to identify charge-disrupting amino acid mutations that were predicted to decrease the stability of the protein. One mutation, OVA-C12R, significantly reduced the half-life of the protein and was preferentially degraded in a 26-S proteasomal-dependent manner. The destabilized ovalbumin protein exhibited enhanced presentation of the major histocompatibility complex (MHC) class I immunogenic epitope, SIINFEKL, on the surface of B16F10 cells or murine bone marrow-derived dendritic cells (BMDCs) in vitro. Enhanced presentation correlated with better recognition by cognate CD8 OT-I T cells as measured by activation, proliferation, and effector cytokine production. Finally, VSV encoding the degradation-prone antigen was better able to prime an antigen ovalbumin-specific CD8 T cell response in vivo without altering the anti-viral CD8 T cell response. Our studies highlight that not only is the choice of antigen in cancer vaccines of importance, but that emphasis should be placed on modifying antigen quality to ensure optimal priming of anti-tumor responses.

Original languageEnglish (US)
Pages (from-to)2540-2552
Number of pages13
JournalMolecular Therapy
Volume28
Issue number12
DOIs
StatePublished - Dec 2 2020

Keywords

  • anti-tumor T cell response, oncolytic virus, viral immunotherapy
  • antigen presentation
  • protein degradation
  • vesicular stomatitis virus

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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