The Quest for the Best: How TCR Affinity, Avidity, and Functional Avidity Affect TCR-Engineered T-Cell Antitumor Responses

Abstract

Over the past decades, adoptive transfer of T cells has revolutionized cancer immunotherapy. In particular, T-cell receptor (TCR) engineering of T cells has marked important milestones in developing more precise and personalized cancer immunotherapies. However, to get the most benefit out of this approach, understanding the role that TCR affinity, avidity, and functional avidity play on how TCRs and T cells function in the context of tumor-associated antigen (TAA) recognition is vital to keep generating improved adoptive T-cell therapies. Aside from TCR-related parameters, other critical factors that govern T-cell activation are the effect of TCR co-receptors on TCR–peptide-major histocompatibility complex (pMHC) stabilization and TCR signaling, tumor epitope density, and TCR expression levels in TCR-engineered T cells. In this review, we describe the key aspects governing TCR specificity, T-cell activation, and how these concepts can be applied to cancer-specific TCR redirection of T cells.

Identification of Cross-Reactive CD8+ T Cell Receptors with High Functional Avidity to a SARS-CoV-2 Immunodominant Epitope and Its Natural Mutant Variants

“…When ectopically transduced, they could elicit CD8 + T cell cytotoxicity upon target cells (Figure 3D), and mediate the activation of T helper type 1 CD4 + T cells to secret cytokines in a CD8-independent manner (Figure 3E). It has been reported that such independency could only be achieved when the TCR exhibited high-affinity binding to the cognate pMHC (Campillo-Davo et al, 2020; Lyons et al, 2006; Tan et al, 2017). In the affinity test of the N 361-369 -specific TCRs in the transduced CD8 + T or CD4 + T cells, we found that their EC50 concentrations ranged from 47.17 nM to 380.9 nM (Figure 4A).…”

“…TCRs. (Campillo-Davo et al, 2020;Lyons et al, 2006;Tan et al, 2017). Activation of T cells independent of the CD8 co-receptor reflects the high functional avidity of their TCRs.…”

“…When TCRs identify the cognate pMHC, together with matching CD8 co-receptor binding to the MHC, the T cells will be activated. Such activation is dependent on the binding kinetics of the TCR-pMHC, which is influenced by the density of processed epitopes on the membrane of the virus-infected cells or antigen presenting cells (APC) (Campillo-Davo et al, 2020; Gonzalez et al, 2005). Particularly, CD8 co-receptor is indispensable for enhanced activation of T cells with low-affinity TCRs, but not for T cells with high-affinity TCRs.…”

“…Particularly, CD8 co-receptor is indispensable for enhanced activation of T cells with low-affinity TCRs, but not for T cells with high-affinity TCRs. (Campillo-Davo et al, 2020; Lyons et al, 2006; Tan et al, 2017). Activation of T cells independent of the CD8 co-receptor reflects the high functional avidity of their TCRs.…”

“…Activation of T cells independent of the CD8 co-receptor reflects the high functional avidity of their TCRs. Hence, the functional avidity of TCRs is a critical parameter to be evaluated for determining the pMHC recognition and posterior T-cell activation, which is essential for the killing of virus-infected cells and effective viral clearance (Campillo-Davo et al, 2020). On the other hand, RNA viruses have a tendency to accumulate mutations over time (Duffy, 2018; Villa et al, 2020), which present challenges for T cell-based vaccine development.…”