Class II-restricted tumor antigens can function to either promote or inhibit vaccine induced protective anti-tumor responses
Elise Alspach1, Danielle M. Lussier1, Matthew M. Gubin1, Jeffrey P. Ward1, 2, Cora D. Arthur1 and Robert D. Schreiber1 1Department of Pathology and Immunology, Washington University School of Medicine, 2Department of Medicine, Division of Oncology, Washington University School of Medicine
We previously demonstrated the ability to identify the therapeutically relevant, immunodominant MHC class I neoepitopes responsible for eliciting CD8 T cell responses to murine T3 MCA sarcoma cells (a G1254V point mutation in Lama4 and a A506T mutation in Alg8).These neoepitopes play a critical role in mediating the in vivo clearance of established T3 tumors following treatment with either checkpoint blockade or neoantigen vaccines. We now show that T3 tumor cells also express point mutations that induce development of helper CD4 T cell responses: a N711Y mutant form of Itgb1 and a G326A mutant form of Eif4a3.CD4 T cell responses to these two neoantigens could be detected in either T3 tumor-bearing mice or in naïve mice vaccinated with synthetic long peptides that contain the point mutations. CD4 T cells that recognize mItgb1 produce IL-2 and IFN when stimulated ex-vivo with irradiated splenocytes pulsed with the neoepitope-containing peptide.Our current hypothesis is that mItgb1 elicits the CD4 Th1 response needed to generate mLama4 specific CTL.Interestingly, we also detected a wild type MHCII binding sequence overlapping the major MHCI restricted mLama4 neoantigen. CD4 T cell responses against this wild type sequence were not observed in T3 tumor-bearing mice but were induced in wild type mice vaccinated with synthetic long peptides encompassing both the mLama4 MHCI neoepitope and the WT MHCII binding sequence. Compared to vaccination with a synthetic long peptide containing both the mLama4-specific CD8 neoepitope and the self CD4 epitope, a peptide vaccine containing an amino acid substitution aimed at ablating the self MHCII epitope resulted in enhanced CD8 T cell cytolytic activity. These results indicate that the immunogenicity of MHCI restricted neoepitopes may be tempered by the presence of wild type sequences that function as Treg epitopes when used in tumor specific vaccines.This observation could explain why certain predicted MHCI neoepitopes do not function as expected in personalized cancer vaccines.
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