Identifying Individual T Cell Receptors of Optimal Avidity for Tumor Antigens.

Michael Hebeisen,Julien Schmidt,Daniel E Speiser,Nathalie Rufer,Mathilde Allard,Philippe O Gannon

doi:10.3389/fimmu.2015.00582

Abstract

Cytotoxic T cells recognize, via their T cell receptors (TCRs), small antigenic peptides presented by the major histocompatibility complex (pMHC) on the surface of professional antigen-presenting cells and infected or malignant cells. The efficiency of T cell triggering critically depends on TCR binding to cognate pMHC, i.e., the TCR–pMHC structural avidity. The binding and kinetic attributes of this interaction are key parameters for protective T cell-mediated immunity, with stronger TCR–pMHC interactions conferring superior T cell activation and responsiveness than weaker ones. However, high-avidity TCRs are not always available, particularly among self/tumor antigen-specific T cells, most of which are eliminated by central and peripheral deletion mechanisms. Consequently, systematic assessment of T cell avidity can greatly help distinguishing protective from non-protective T cells. Here, we review novel strategies to assess TCR–pMHC interaction kinetics, enabling the identification of the functionally most-relevant T cells. We also discuss the significance of these technologies in determining which cells within a naturally occurring polyclonal tumor-specific T cell response would offer the best clinical benefit for use in adoptive therapies, with or without T cell engineering.

Highlights

Cytotoxic T cells recognize, via their T cell receptors (TCRs), small antigenic peptides presented by the major histocompatibility complex on the surface of professional antigen-presenting cells and infected or malignant cells
The efficiency of T cell triggering critically depends on TCR binding to cognate presented by the major histocompatibility complex (pMHC), i.e., the TCR–pMHC structural avidity
Major breakthroughs were made for melanoma patients [1,2,3,4], and progress becomes evident for patients with frequent diseases, such as lung and kidney cancer [5]

Summary

NY-ESO1-spec TCR variantsb

Until a supraphysiological TCR affinity thresholdd aTCRs were transfected/transduced within human primary CD8 T cells. bTCRs were transfected/transduced within human SUP-T1 cells. cTCRs were transfected/transduced within mouse CD8+/− splenocytes. dCorrelation between TCR–pMHC affinity and T cell functionality is not linear with a functional decline for TCR–pMHC interactions taking place beyond the physiological affinity range at KD < 1 μM. The NTAmer offers the real-time quantification of dissociation kinetics on a wide range of TCR–pMHC affinities directly at the surface of living, primary CD8 T cells, providing rapid, easy, and direct measurements of the monomeric TCR– pMHC dissociation rates within large numbers of tumor-specific CD8 T cell clones [41, 42] (Figure 4). We and others demonstrate that within the range of physiological interactions (KD 100–1 μM), the TCR–pMHC affinity (as determined by SPR) strongly correlates with various T cell functional read-outs [59, 60, 65,66,67, 73, 76, 80, 81, 83, 84] These include T cell potency for target cell conjugation, phosphorylation of downstream molecules of the TCR-signaling complex, intracellular Ca2+ mobilization, lytic-granule polarization, target cell killing, cytokine production, cell proliferation, polyfunctionality, in vivo tumor infiltration, and protection/survival. We report the feasibility and usefulness of TCR–pMHC structural avidity assessment by NTAmers of naturally occurring polyclonal T cell responses, allowing the identification and selection of rare high-avidity cytotoxic T cells from patients for cancer therapy

A New Look at Old Questions

Findings

CONCLUSIVE REMARKS