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TCR-ligand dissociation rate is a robust and stable biomarker of CD8+ T cell potency
Mathilde Allard, … , Michael Hebeisen, Nathalie Rufer
Mathilde Allard, … , Michael Hebeisen, Nathalie Rufer
Published July 20, 2017
Citation Information: JCI Insight. 2017;2(14):e92570. https://doi.org/10.1172/jci.insight.92570.
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Categories: Clinical Medicine Immunology Therapeutics

TCR-ligand dissociation rate is a robust and stable biomarker of CD8+ T cell potency

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Abstract

Despite influencing many aspects of T cell biology, the kinetics of T cell receptor (TCR) binding to peptide-major histocompatibility molecules (pMHC) remain infrequently determined in patient monitoring or for adoptive T cell therapy. Using specifically designed reversible fluorescent pMHC multimeric complexes, we performed a comprehensive study of TCR-pMHC off-rates combined with various functional assays on large libraries of self/tumor– and virus-specific CD8+ T cell clones from melanoma patients and healthy donors. We demonstrate that monomeric TCR-pMHC dissociation rates accurately predict the extent of cytotoxicity, cytokine production, polyfunctionality, cell proliferation, activating/inhibitory receptor expression, and in vivo antitumor potency of naturally occurring antigen-specific CD8+ T cells. Our data also confirm the superior binding avidities of virus-specific T cells as compared with self/tumor–specific T cell clonotypes (n > 300). Importantly, the TCR-pMHC off-rate is a more stable and robust biomarker of CD8+ T cell potency than the frequently used functional assays/metrics that depend on the T cell’s activation state, and therefore show major intra- and interexperimental variability. Taken together, our data show that the monomeric TCR-pMHC off-rate is highly useful for the ex vivo high-throughput functional assessment of antigen-specific CD8+ T cell responses and a strong candidate as a biomarker of T cell therapeutic efficacy.

Authors

Mathilde Allard, Barbara Couturaud, Laura Carretero-Iglesia, Minh Ngoc Duong, Julien Schmidt, Gwennaëlle C. Monnot, Pedro Romero, Daniel E. Speiser, Michael Hebeisen, Nathalie Rufer

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Figure 1

Relationship between TCR dissociation rates and functional avidity of self/tumor– and virus-specific CD8+ T cell clones.

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Relationship between TCR dissociation rates and functional avidity of se...
Correlations between EC50 values from (A) killing, (B) CD107a degranulation, (C) IFN-γ–, (D) TNF-α–, and (E) IL-2–production titration assays and NTAmer-derived TCR dissociation rates (koff). (F) Correlations between percentages of proliferating cells upon antigen-specific stimulation and NTAmer-derived TCR dissociation rates (koff). (A–F) Antigen-specific CD8+ T cell clones were generated upon direct ex vivo sorting from effector-memory (EM)/CD28+/– and/or EMRA/CD28–subsets. Each data point represents an A2/Melan-A26–35– (derived from patient LAU618, ○), A2/NY-ESO-1157–165– (patient LAU155, □), A2/pp65495–504–, or A2/BMFL1259–267– (healthy donor BCL4, ◊) specific individual T cell clone. Nonfunctional clones are represented in gray boxes. The number of clones displaying function n, as well as Spearman’s correlation (2 tailed, α = 0.05) coefficients R and P values are indicated. Color-coded and black lines are indicative of regression fitting and 95% confidence intervals, respectively. Of note, only very low numbers of outliers were identified when applying the ROUT method and are highlighted in color (71). The representative TCR-BV-CDR3 clonotype diversity of each antigenic specificity was LAU618/Melan-A, 77%; LAU155/NY-ESO-1, 43%; BCL4/pp65, 57%; and BCL4/BMFL1, 67%.
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