Relating TCR-peptide-MHC affinity to immunogenicity for the design of tumor vaccines
Rachel H. McMahan, … , Darcy B. Wilson, Jill E. Slansky
Rachel H. McMahan, … , Darcy B. Wilson, Jill E. Slansky
Published September 1, 2006
Citation Information: J Clin Invest. 2006;116(9):2543-2551. https://doi.org/10.1172/JCI26936.
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Relating TCR-peptide-MHC affinity to immunogenicity for the design of tumor vaccines

Abstract

One approach to enhancing the T cell response to tumors is vaccination with mimotopes, mimics of tumor epitopes. While mimotopes can stimulate proliferation of T cells that recognize tumor-associated antigens (TAAs), this expansion does not always correlate with control of tumor growth. We hypothesized that vaccination with mimotopes of optimal affinity in this interaction will improve antitumor immunity. Using a combinatorial peptide library and a cytotoxic T lymphocyte clone that recognizes a TAA, we identified a panel of mimotopes that, when complexed with MHC, bound the TAA-specific TCR with a range of affinities. As expected, in vitro assays showed that the affinity of the TCR-peptide-MHC (TCR-pMHC) interaction correlated with activity of the T cell clone. However, only vaccination with mimotopes in the intermediate-affinity range elicited functional T cells and provided protection against tumor growth in vivo. Vaccination with mimotopes with the highest-affinity TCR-pMHC interactions elicited TAA-specific T cells to the tumor, but did not control tumor growth at any of the peptide concentrations tested. Further analysis of these T cells showed functional defects in response to the TAA. Thus, stimulation of an antitumor response by mimotopes may be optimal with peptides that increase but do not maximize the affinity of the TCR-pMHC interaction.

Authors

Rachel H. McMahan, Jennifer A. McWilliams, Kimberly R. Jordan, Steven W. Dow, Darcy B. Wilson, Jill E. Slansky

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Figure 2

Mimotopes potently activate the T cell clone.

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Mimotopes potently activate the T cell clone. The T cell clone was cultu...
The T cell clone was cultured with increasing concentrations of the AH1 peptide, mimotopes, or the negative control β-gal peptide. (A) Production of IFN-γ, as determined by ELISA, from the T cell clone in response to incubation for 24 hours with the indicated peptide. (B) After 24 hours, 3H-thymidine was added to the cultures, and 3H-thymidine incorporation was measured at 48 hours. Data are representative of 2 experiments per peptide, and each data point was performed in triplicate and averaged. ND, no data (EC50 was too low to be determined).