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

Diana Campillo-Davo,Donovan Flumens,Eva Lion

doi:10.3390/cells9071720

Diana Campillo-Davo, Donovan Flumens + Show 1 more

Open Access

https://doi.org/10.3390/cells9071720

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Journal: Cells	Publication Date: Jul 18, 2020
Citations: 56	License type: CC BY 4.0

Affiliation: University of Antwerp, Antwerp University Hospital

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.

Highlights

Introduction to TCRAffinity, Avidity, and Functional AvidityFrom tumor infiltrating lymphocytes to T-cell receptor (TCR) and chimeric antigen receptor (CAR)T-cell engineering, T cells have marked important milestones in cancer immunotherapy [1]
T-cell activation is dependent on the binding kinetics of the TCR–peptide-major histocompatibility complex (pMHC), which in turn is influenced by the epitope density on the membrane of the tumor cell or antigen-presenting cell (APC) [15]
L antigen family member 1 (LAGE-1), overexpressed tumor-associated antigen (TAA), or differentiation-associated TAAs [20,21,22]. This technique has shown that naturally-processed TAA peptide epitopes are usually presented at ratios of 10 to 150 copies per cell [20]. These numbers would be sufficient for antigen-specific T cells as it has been demonstrated that one single TCR–pMHC interaction can induce T-cell activation in helper T cells [23]

Summary

The Role of Epitope Density

T-cell activation is dependent on the binding kinetics of the TCR–pMHC, which in turn is influenced by the epitope density on the membrane of the tumor cell or antigen-presenting cell (APC) [15]. This technique has shown that naturally-processed TAA peptide epitopes are usually presented at ratios of 10 to 150 copies per cell [20] These numbers would be sufficient for antigen-specific T cells as it has been demonstrated that one single TCR–pMHC interaction can induce T-cell activation in helper T cells [23]. A study by Jaigirdar and colleagues indicated that high-avidity TCRs against the leukemia antigen Wilms’ tumor 1 (WT1) could not recognize naturally processed WT1 peptides [30] These divergent studies highlight the complexity of TCR–pMHC interactions in the context of cancer recognition and the risk of oversimplifying the selection of T-cell clones or TCRs for TCR-engineering to the best TCR affinity or avidity

The Role of TCR Co-Receptors

Selection of Cancer-Specific TCRs

Improvement of TCR-Engineered T-Cell Antitumor Responses

Enhancementofof tumor-specific tumor-specific T-cellT-cell receptorreceptor

Conclusions and Future Perspectives

Methods