Immunogenicity of self tumor associated proteins is enhanced through protein truncation

Tim Kottke, Kevin G. Shim, Vanesa Alonso-Camino, Shane Zaidi, Rosa Maria Diaz, Jose Pulido, Jill Thompson, Karishma R. Rajani, Laura Evgin, Elizabeth Ilett, Hardev Pandha, Kevin Harrington, Peter Selby, Alan Melcher, Richard Vile

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

We showed previously that therapy with Vesicular Stomatitis Virus (VSV) expressing tumor-associated proteins eradicates established tumors. We show here that when cellular cDNA were cloned into VSV which retained their own poly-A signal, viral species emerged in culture which had deleted the cellular poly-A signal and also contained a truncated form of the protein coding sequence. Typically, the truncation occurred such that a Tyrosine-encoding codon was converted into a STOP codon. We believe that the truncation of tumor-associated proteins expressed from VSV in this way occurred to preserve the ability of the virus to replicate efficiently. Truncated cDNA expressed from VSV were significantly more effective than full length cDNA in treating established tumors. Moreover, tumor therapy with truncated cDNA was completely abolished by depletion of CD4+ T cells, whereas therapy with full length cDNA was CD8+ T cell dependent. These data show that the type/potency of antitumor immune responses against self-tumor-associated proteins can be manipulated in vivo through the nature of the self protein (full length or truncated). Therefore, in addition to generation of neoantigens through sequence mutation, immunological tolerance against self-tumor-associated proteins can be broken through manipulation of protein integrity, allowing for rational design of better self-immunogens for cancer immunotherapy.

Original languageEnglish (US)
Article number16030
Pages (from-to)16030
Number of pages1
JournalMolecular Therapy - Oncolytics
Volume3
DOIs
StatePublished - Dec 7 2016

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research
  • Pharmacology (medical)

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  • Cite this

    Kottke, T., Shim, K. G., Alonso-Camino, V., Zaidi, S., Maria Diaz, R., Pulido, J., Thompson, J., Rajani, K. R., Evgin, L., Ilett, E., Pandha, H., Harrington, K., Selby, P., Melcher, A., & Vile, R. (2016). Immunogenicity of self tumor associated proteins is enhanced through protein truncation. Molecular Therapy - Oncolytics, 3, 16030. [16030]. https://doi.org/10.1038/mto.2016.30