title: Immunogenicity of self tumor associated proteins is enhanced through protein truncation.
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 manipulatedin vivothrough 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.
authors.affiliation: Department of Molecular Medicine, Mayo Clinic , Rochester, Minnesota, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Kottke
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA; Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Shim
authors.affiliation: Department of Molecular Medicine, Mayo Clinic , Rochester, Minnesota, USA.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Alonso-Camino
authors.affiliation: Department of Molecular Medicine, Mayo Clinic , Rochester, Minnesota, USA.
authors.forename: Shane
authors.initials: S
authors.lastname: Zaidi
authors.affiliation: Department of Molecular Medicine, Mayo Clinic , Rochester, Minnesota, USA.
authors.forename: Rosa
authors.initials: R
authors.lastname: Maria Diaz
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA; Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Pulido
authors.affiliation: Department of Molecular Medicine, Mayo Clinic , Rochester, Minnesota, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Thompson
authors.affiliation: Department of Molecular Medicine, Mayo Clinic , Rochester, Minnesota, USA.
authors.forename: Karishma R
authors.initials: KR
authors.lastname: Rajani
authors.affiliation: Department of Molecular Medicine, Mayo Clinic , Rochester, Minnesota, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Evgin
authors.affiliation: Cancer Research UK Clinical Center, St. James' University Hospital , Leeds, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ilett
authors.affiliation: University of Surrey, Guildford , UK.
authors.forename: Hardev
authors.initials: H
authors.lastname: Pandha
authors.affiliation: The Institute of Cancer Research , London, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Harrington
authors.affiliation: Cancer Research UK Clinical Center, St. James' University Hospital , Leeds, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Selby
authors.affiliation: The Institute of Cancer Research , London, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Melcher
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA; Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA; Cancer Research UK Clinical Center, St. James' University Hospital, Leeds, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Vile