TY - JOUR
T1 - Vesicular Stomatitis Virus Encoding a Destabilized Tumor Antigen Improves Activation of Anti-tumor T Cell Responses
AU - Huff, Amanda L.
AU - Evgin, Laura
AU - Thompson, Jill
AU - Kottke, Tim
AU - Driscoll, Christopher B.
AU - Tonne, Jason
AU - Wongthida, Phonphimon
AU - Schuelke, Matthew
AU - Shim, Kevin G.
AU - Mer, Georges
AU - Ramirez-Alvarado, Marina
AU - Vile, Richard
N1 - Publisher Copyright:
© 2020
PY - 2020/12/2
Y1 - 2020/12/2
N2 - 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.
AB - 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.
KW - anti-tumor T cell response, oncolytic virus, viral immunotherapy
KW - antigen presentation
KW - protein degradation
KW - vesicular stomatitis virus
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UR - http://www.scopus.com/inward/citedby.url?scp=85090127308&partnerID=8YFLogxK
U2 - 10.1016/j.ymthe.2020.08.013
DO - 10.1016/j.ymthe.2020.08.013
M3 - Article
C2 - 32877695
AN - SCOPUS:85090127308
SN - 1525-0016
VL - 28
SP - 2540
EP - 2552
JO - Molecular Therapy
JF - Molecular Therapy
IS - 12
ER -