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Peptide Anchor Modifications Modulate T Cell Receptor Recognition of a Melanoma-Associated Antigen

thesis
posted on 2021-03-08, 00:00 authored by Angela R. Smith

T cells expressing T cell receptors (TCRs) can identify and eliminate foreign pathogens by recognizing peptides presented by major histocompatibility complex (MHC) proteins. The association between peptide binding affinity and immunogenicity has led to the engineering of modified peptides with improved MHC binding, with the hope that these peptides would be useful for eliciting cross-reactive immune responses directed toward their weak binding, unmodified counterparts. However, increasing evidence indicates that TCRs can perceive such anchor-modified peptides differently than wild-type (WT) peptides.

Here, I characterized how different TCRs recognize the WT and anchor-modified variants of the well-known gp100209 melanoma tumor antigen. I show here that, unexpectedly, mutational modifications at the first primary anchor position can lead to substantially stronger or weaker TCR binding. Surprisingly, the effect of anchor modification can be sensed by a TCR at regions far from the site of modification, indicating a through-protein mechanism in which the anchor residue serves as an allosteric modulator of TCR binding.

Of the panel of TCRs, the SILv44 receptor has been proposed as a clinical candidate for immunotherapy of melanoma. Finding that gp100209-specific TCRs are sensitive to peptide anchor modifications, I show that, in contrast to previously published work, the enhanced tumor control properties of the SILv44 TCR are a result of strong TCR binding affinity to the WT peptide antigen. Overall, my studies highlight how subtle changes at a primary peptide anchor position can have dramatic and TCR-dependent consequences and should help guide the development of TCR and T cell-based therapeutics.

History

Date Modified

2021-04-08

Defense Date

2021-02-25

CIP Code

  • 26.0202

Research Director(s)

Brian M. Baker

Committee Members

Jessica Brown Patricia Clark

Degree

  • Doctor of Philosophy

Degree Level

  • Doctoral Dissertation

Alternate Identifier

1245390937

Library Record

6001792

OCLC Number

1245390937

Additional Groups

  • Chemistry and Biochemistry

Program Name

  • Chemistry and Biochemistry

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