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• W3164955761 abstract "Tumors frequently express unmutated self-tumor-associated antigens (self-TAAs). However, trial results using self-TAAs as vaccine targets against cancer are mixed, often attributed to deletion of T cells with high-affinity receptors (TCRs) for self-TAAs during T cell development. Mutating these weak self-TAAs to produce higher affinity, effective vaccines is challenging, since the mutations may not benefit all members of the broad self-TAA-specific T cell repertoire. We previously identified a common weak murine self-TAA that we converted to a highly effective antitumor vaccine by a single amino acid substitution. In this case the modified and natural self-TAAs still raised very similar sets of CD8 T cells. Our structural studies herein show that the modification of the self-TAA resulted in a subtle change in the major histocompatibility complex I-TAA structure. This amino acid substitution allowed a dramatic conformational change in the peptide during subsequent TCR engagement, creating a large increase in TCR affinity and accounting for the efficacy of the modified self-TAA as a vaccine. These results show that carefully selected, well-characterized modifications to a poorly immunogenic self-TAA can rescue the immune response of the large repertoire of weakly responding natural self-TAA-specific CD8 T cells, driving them to proliferate and differentiate into functional effectors. Subsequently, the unmodified self-TAA on the tumor cells, while unable to drive this response, is nevertheless a sufficient target for the CD8 cytotoxic effectors. Our results suggest a pathway for more efficiently identifying variants of common self-TAAs, which could be useful in vaccine development, complementing other current nonantigen-specific immunotherapies." @default.
• W3164955761 created "2021-06-07" @default.
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• W3164955761 date "2021-05-31" @default.
• W3164955761 modified "2023-09-23" @default.
• W3164955761 title "Structures suggest an approach for converting weak self-peptide tumor antigens into superagonists for CD8 T cells in cancer" @default.
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• W3164955761 doi "https://doi.org/10.1073/pnas.2100588118" @default.
• W3164955761 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8201969" @default.
• W3164955761 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34074778" @default.
• W3164955761 hasPublicationYear "2021" @default.
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