Structures suggest an approach for converting weak self-peptide tumor antigens into superagonists for CD8 T cells in cancer

Proc Natl Acad Sci U S A. 2021 Jun 8;118(23):e2100588118. doi: 10.1073/pnas.2100588118.


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.

Keywords: T cell receptor; agonistic peptide; crystal structure; peptide–MHC–TCR interaction; tumor-associated antigens.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology*
  • Autoantigens / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cancer Vaccines / immunology
  • Cell Line, Tumor
  • Female
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms, Experimental / immunology*
  • Neoplasms, Experimental / prevention & control
  • Peptides / immunology*
  • Receptors, Antigen, T-Cell / immunology*
  • Sf9 Cells
  • Spodoptera


  • Antigens, Neoplasm
  • Autoantigens
  • Cancer Vaccines
  • Peptides
  • Receptors, Antigen, T-Cell