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.

Keywords: T-cell fitness; T-cell receptor; TCR affinity; TCR avidity; TCR engineering; affinity-enhanced; cancer immunotherapy.

Figure 1

The interaction between the T-cell receptor (TCR) and the peptide-major histocompatibility complex (pMHC). T cells recognize tumor peptide epitopes via the pMHC. Different parameters affect the sensitivity that T cells, including T-cell receptor (TCR)-engineered T cells, will display against the pMHC. TCR affinity describes the strength of the interaction between a single TCR and pMHC. It is commonly measured using a technique named surface plasmon resonance. TCR avidity, on the other hand, reflects the contact of multiple TCRs and pMHCs. For this reason, multimers consisting of a number of pMHCs linked via streptavidin–biotin complexes to a fluorochrome are used to stain antigen-specific T cells and measure their TCR avidity. This parameter also takes into account the effect of T-cell co-receptors such as CD8 in the stabilization of TCR–pMHC binding. Closely related to TCR avidity, functional avidity shows the T-cell fitness to a target antigen in terms of its activation and effector functions, namely, T-cell proliferation, antitumor cytotoxicity, cytokine production, upregulation of activation markers, among others.

Figure 2

Enhancement of tumor-specific T-cell receptor (TCR)-engineered T cells. The antitumor functionality of TCR-engineered T cells can be leveraged by improving the affinity of the TCR–peptide-major histocompatibility complex (pMHC) interaction via TCR affinity maturation processes, such as phage display or the substitution of key amino acids in the complementarity-determining regions (CDRs) of the TCR. On another note, the presence of native and transgenic TCRs can lead to the mispairing of their TCR chains that reduce the levels of transgenic TCR on the surface of the T cells. To overcome this problem, the presence of native TCRs can be either downregulated by silencing RNAs targeting the TCR constant sequences in mRNA transcripts or completely abrogated with tools such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), or the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system. These techniques can be combined with the improvement of TCR pairing by addition of disulfide bonds, the murinization of TCR αβ constant domains, or the use of TCR γδ domains in the TCR αβ. Finally, systems in which the two TCR chains are transformed into one single TCR chain can also ensure that mispairing with the native TCRs does not occur without the need to abolish its expression.