Molecular properties of gp100‐reactive T‐cell receptors drive the cytokine profile and antitumor efficacy of transgenic host T cells. (13th August 2018)

• Record Type: Journal Article
• Authors: Eby, Jonathan M.; Smith, Angela R.; Riley, Timothy P.; Cosgrove, Cormac; Ankney, Christian M.; Henning, Steven W.; Paulos, Chrystal M.; Garrett‐Mayer, Elizabeth; Luiten, Rosalie M.; Nishimura, Michael I.; Baker, Brian M.; Le Poole, I. Caroline
• Is Part Of: Pigment cell & melanoma research. Volume 32:Number 1(2019)
• Page Start: 68
• Page End: 78
• Publication Date: 2018-08-13
• Subjects: IL‐17A -- melanoma -- molecular modeling -- T‐cell receptor -- transgenic T cells; Melanoma -- Periodicals; Chromatophores -- Periodicals; Animal pigments -- Periodicals; 616.99477
• DOI: 10.1111/pcmr.12724
• Languages: English
• ISSNs: 1755-1471

Abstract

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.