Molecular properties of gp100-reactive T-cell receptors drive the cytokine profile and antitumor efficacy of transgenic host T cells

Jonathan M. Eby, Angela R. Smith, Timothy P. Riley, Cormac Cosgrove, Christian M. Ankney, Steven W. Henning, Chrystal M. Paulos, Elizabeth Garrett-Mayer, Rosalie M. Luiten, Michael I. Nishimura, Brian M. Baker, I. Caroline Le Poole*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

To study the contribution of T-cell receptors (TCR) to resulting T-cell responses, we studied three different human αβ TCRs, reactive to the same gp100-derived peptide presented in the context of HLA-A*0201. When expressed in primary CD8 T cells, all receptors elicited classic antigen-induced IFN-γ responses, which correlated with TCR affinity for peptide–MHC in the order T4H2 > R6C12 > SILv44. However, SILv44 elicited superior IL-17A release. Importantly, in vivo, SILv44-transgenic T cells mediated superior antitumor responses to 888-A2 + human melanoma tumor cells upon adoptive transfer into tumor-challenged mice while maintaining IL-17 expression. Modeling of the TCR ternary complexes suggested architectural differences between SILv44 and the other complexes, providing a potential structural basis for the observed differences. Overall, the data reveal a more prominent role for the T-cell receptor in defining host T-cell physiology than traditionally assumed, while parameters beyond IFN-γ secretion and TCR affinity ultimately determine the reactivity of tumor-reactive T cells.

Original languageEnglish (US)
Pages (from-to)68-78
Number of pages11
JournalPigment Cell and Melanoma Research
Volume32
Issue number1
DOIs
StatePublished - Jan 2019

Keywords

  • IL-17A
  • T-cell receptor
  • melanoma
  • molecular modeling
  • transgenic T cells

ASJC Scopus subject areas

  • Oncology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Dermatology

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  • Cite this

    Eby, J. M., Smith, A. R., Riley, T. P., Cosgrove, C., Ankney, C. M., Henning, S. W., Paulos, C. M., Garrett-Mayer, E., Luiten, R. M., Nishimura, M. I., Baker, B. M., & Le Poole, I. C. (2019). Molecular properties of gp100-reactive T-cell receptors drive the cytokine profile and antitumor efficacy of transgenic host T cells. Pigment Cell and Melanoma Research, 32(1), 68-78. https://doi.org/10.1111/pcmr.12724