How TCR Affinity, Avidity, and Functional Avidity Affect TCR
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cells Review The Quest for the Best: How TCR Affinity, Avidity, and Functional Avidity Affect TCR-Engineered T-Cell Antitumor Responses Diana Campillo-Davo 1,*, Donovan Flumens 1 and Eva Lion 1,2 1 Tumor Immunology Group, Laboratory of Experimental Hematology, Vaccine & Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, 2610 Antwerp, Belgium; [email protected] (D.F.); [email protected] (E.L.) 2 Center for Cell Therapy & Regenerative Medicine, Antwerp University Hospital, 2650 Edegem, Belgium * Correspondence: [email protected]; Tel.: +32-(0)38215254 Received: 16 June 2020; Accepted: 15 July 2020; Published: 18 July 2020 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 receptor; TCR affinity; TCR avidity; TCR engineering; T-cell fitness; affinity-enhanced; cancer immunotherapy 1. Introduction to TCR Affinity, Avidity, and Functional Avidity From 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 cells recognize short peptide epitopes in the context of the major histocompatibility complex (MHC) thanks to their TCR. This receptor is a heterodimer of the immunoglobulin gene superfamily composed of two different alpha and beta polypeptides in conventional αβ T cells. The extracellular domain, which is involved in antigen recognition, comprises a variable region, a constant region, and a hinge, where a disulfide bridge is located to stabilize the interaction between the TCR chains. It continues into the transmembrane region and the intracellular domain, which interacts noncovalently with CD3 γ, δ, ", and ζ proteins to form the TCR–CD3 complex. When a TCR correctly identifies the cognate peptide-MHC complex (pMHC), including the correct matching between MHC type and CD4/CD8 co-receptor, the TCR undergoes a series of conformational changes that lead to a first activation signal [2]. Three different TCR parameters are the major players governing this pMHC recognition and posterior T-cell activation, namely, TCR affinity, avidity, and functional avidity (Figure1). TCR affinity is a key factor in controlling the sensitivity of the T cells towards the antigen and it is defined as the strength of the interaction between a single TCR and the pMHC ligand [3]. It is usually determined by the association (kon) and dissociation rates (koff) and represented as the equilibrium Cells 2020, 9, 1720; doi:10.3390/cells9071720 www.mdpi.com/journal/cells Cells 2020, 9, 1720 2 of 18 Cells 2020, 9, x 2 of 18 dissociation constant (KD)[3]. If TCR affinity relates to single receptors, TCR avidity measures the strengthmeasures of multiplethe strength TCR–pMHC of multiple engagements TCR–pMHC and considers engagements the eff ectand of considers other molecules the effect such of as TCRother co-receptorsmolecules such in the as interaction, TCR co-receptors whereas in functional the interaction, avidity whereas represents functional the T-cell avidity fitness represents and activity theat T- dicellfferent fitness concentrations and activity at of different peptide epitope.concentrations The mean of peptide functional epitope. avidity The is mean usually functional described avidity as an is EC50usually concentration, described as representing an EC50 concentration the peptide, representing dose at which the a peptide half-maximal dose at activation which a half of the-maximal T-cell populationactivation isof reached the T-cell [4]. population Although physiologicalis reached [4] TCR. Although affinities physiological can range from TCR 1 µ affinitiesM to 100 canµM[ range5,6], severalfrom 1studies µM to 100 have µM marked [5,6], theseveral threshold studies of have affinity marked for maximal the threshold T-cell activity,of affinity including for maximal antitumor T-cell T-cellactivity, responses, including at 5–10antitumorµM of T peptide-cell responses, epitope [at3, 56–108]. µM In a of comparative peptide epitope study [3,6 of– native8]. In a TCRs comparative with a TCR-likestudy of CAR,native it TCRs was evidencedwith a TCR that-like the CAR affi, itnity was of evidenced the antibody that fragmentthe affinity in of the the TCR-like antibody CAR fragment was determinantin the TCR-like to achieve CAR was better determinant T-cell responses. to achieve In thisbetter study, T-cell and responses. similarly In to this the study, ones performed and similarly by Zhongto the etones al. performed [6], TCR a ffibynity Zhong could et al. not [6] be, TCR improved affinity above could 5 notµM, be whereas improved TCR-like above 5 CARs µM, whereas would displayTCR-like an CARs improved would affi displaynity threshold an improve in thed affinity nM range threshold [7]. Conversely, in the nM arange comparison [7]. Conversely, between a conventionalcomparison between high-affi conventionalnity single-chain high TCRs-affinity and single TCR-like-chain CARs TCRs revealed and TCR that,-like althoughCARs revealed TCR-like that, CARsalthough expression TCR-like levels CARs were expression higher, they levels were were less higher, sensitive they in recognizingwere less sensitive the ligand, in recognizing which can bethe potentialligand, which attributed can tobe their potential signaling attributed kinetics to [ 9their]. In asignaling panel of TCRskinetics with [9] enhanced. In a panel affi ofnities TCRs within with theenhanced physiological affinities range within against the physiological the cancer/testis range antigen against (CTA) the cancer/testis New York esophageal antigen (CTA) squamous New York cell carcinomaesophageal 1 (NY-ESO-1),squamous cell TCR-transduced carcinoma 1 T(NY cells-ESO could-1), respondTCR-transduced to affinities T cells above could 5 µM, respond showing to thataffinities affinity ab canove limit5 µM, the showing maximal that activation affinity can of limit T cells the [ 8maximal]. This fact activation is likely of caused T cells by[8]. aThis reduced fact is contributionlikely caused of by the a TCR reduced affinity contribution to TCR avidity of the above TCR theaffinity threshold to TCR [6]. avidity Furthermore, above the a computational threshold [6]. analysisFurthermore, from 12 a phenotypiccomputational models analysis of TCR–pMHC from 12 phenotypic interactions showedmodels thatof TCR TCR–pMHC affinity interactions would not beshowed a reliable that marker TCR affinity for T-cell would responses not be [ 10a reliable]. marker for T-cell responses [10]. Figure 1. The interaction between the T-cell receptor (TCR) and the peptide-major histocompatibility complexFigure 1. (pMHC). The interaction T cells recognize between tumorthe T-cell peptide receptor epitopes (TCR via) and the the pMHC. peptide Di-ffmajorerent histocompatibility parameters affect thecomplex sensitivity (pMHC that). T Tcells, cells recognize including tumor T-cell receptorpeptide epitopes (TCR)-engineered via the pMHC T cells,. 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