T cell receptor binding affinity governs the functional profile of cancer-specific CD8+ T cells

Abstract

Antigen-specific T cell receptor (TCR) gene transfer via patient-derived T cells is an attractive approach to cancer therapy, with the potential to circumvent immune regulatory networks. However, high-affinity tumour-specific TCR clonotypes are typically deleted from the available repertoire during thymic selection because the vast majority of targeted epitopes are derived from autologous proteins. This process places intrinsic constraints on the efficacy of T cell-based cancer vaccines and therapeutic strategies that employ naturally generated tumour-specific TCRs. In this study, we used altered peptide ligands and lentivirus-mediated transduction of affinity-enhanced TCRs selected by phage display to study the functional properties of CD8+ T cells specific for three different tumour-associated peptide antigens across a range of binding parameters. The key findings were: (i) TCR affinity controls T cell antigen sensitivity and polyfunctionality; (ii) supraphysiological affinity thresholds exist, above which T cell function cannot be improved; and (iii) T cells transduced with very high-affinity TCRs exhibit cross-reactivity with self-derived peptides presented by the restricting human leucocyte antigen. Optimal system-defined affinity windows above the range established for natural tumour-specific TCRs therefore allow the enhancement of T cell effector function without off-target effects. These findings have major implications for the rational design of novel TCR-based biologics underpinned by rigorous preclinical evaluation.

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

“…Studies performed over the last two decades have focused on empirically mapping the relationship between pMHC affinity and T-cell activation (5,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). A number of studies have reported an optimal pMHC affinity for T-cell activation, but other studies have failed to observe the optimum.…”

Identification of Rare High-Avidity, Tumor-Reactive CD8+ T Cells by Monomeric TCR–Ligand Off-Rates Measurements on Living Cells

“…Efficient triggering of T-cell responses critically depends on the strength of TCR-mediated antigen recognition, namely it has been shown that strong binding to pMHC confers superior effector function than weak interactions (2)(3)(4)(5)(6)(7). This is of particular interest for immunotherapy based on adoptive T-cell transfer, aiming to convey immune reactivity against tumorassociated antigens, for which endogenous T-cell responses are usually weak.…”

Adoptive T-Cell Therapy for Cancer in the United Kingdom: A Review of Activity for the British Society of Gene and Cell Therapy Annual Meeting 2015

“…Use of TCRs with super-enhanced affinities (K D < 1 nM) in this way is not recommended as these receptors are usually selfreactive. 59 Nevertheless, the phage enhancement process allows generation of TCRs with a whole range of affinities that can be optimized via a rigorous preclinical evaluation process. 59 High-affinity tumor-specific TCR clonotypes are often deleted from the repertoire as most targeted cancer epitopes are derived from self-proteins.…”

“…59 Nevertheless, the phage enhancement process allows generation of TCRs with a whole range of affinities that can be optimized via a rigorous preclinical evaluation process. 59 High-affinity tumor-specific TCR clonotypes are often deleted from the repertoire as most targeted cancer epitopes are derived from self-proteins. Indeed, there is a wide affinity gap between TCRs that target pathogenderived epitopes and those that target self-epitopes.…”

“…TCR binding affinity governs the functional profile of TCR-transduced cancerspecific CD8 + T-cells, with optimal ''anti-pathogen-like'' TCRs being more sensitive to antigen and generating a wider range of functions in response to tumor cells. 59 Adaptimmune have also used their affinity enhancement techniques to select out HIV-specific TCRs that can recognize all known escape variants of the virus, 61 and the future of this approach looks bright. Adaptimmune are currently conducting phase I/II trials of T-cells expressing enhanced NY-ESO-1-specific TCRs.…”