6.7.1 The Basic Structure and Mechanism of TCR-T C...
The potency of TCRs relies on their interaction with peptide-major histocompatibility complex(pMHC), complexes formed by peptide bound to MHC.Intracellular antigens are cut up into peptide chains and displayed by MHC molecules to form pMHCs.Cytoplasmic proteins to be expressed by class I MHC proteins, most of which are defective ribosomal translation products, are cleaved into peptide chains by proteolysis.These peptides are then bound to class I MHC proteins,which are expressed on all nucleated cells’ surface.Some cells, called antigen-presenting cells(APCs), express class II MHC proteins.They internalize foreign material proteins by endocytosis and cleave them into peptide chains to bind with class II MHC proteins.T-cell receptors from T cells, which must be matched to human leukocyte antigen (HLA) alleles of patients, recognize these pMHCs and cause the killing of cancer cells [174-176].
TCR is a heterodimer composed of 2 different transmembrane polypeptide chains: an α chain and a β chain, each consisting of a constant region, which anchors the chain inside the T-cell surface membrane, and a variable region, which recognizes and binds to the antigen presented by MHCs(Figure 6.13).The TCR complex is associated with 6 polypeptides forming 2 heterodimers, CD3γε and CD3δε, and 1 homodimer CD3 ζ, which together forms the CD3 complex.In total, the CD3 complex contains 10 ITAMs, which take part in T-cell activation.Additional costimulatory signals are also essential to the full execution of T-cell function, including CD8 on the surface of cytotoxic T cells, which binds to class I MHC complex, and CD4 on the surface of helper T cells,which binds to class II MHC complex.There are also other well-studied costimulatory molecules including CD28 involved in CD28: B7 engagement on APCs and 4-1BB (CD137) that upregulate antiapoptotic factors to promote T-cell survival when binding with ligands on the surface of APCs.Co-inhibitory molecules, such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), are also part of the T-cell system in charge of extinguishing T-cell signaling [177,178].
(https://www.daowen.com)
Figure 6.13 Structural Components of T Cell Receptor (TCR) and Chimeric Antigen Recepto r(CAR) Signaling.(A) TCRs comprise an αβ heterodimer that binds to peptide major histocompatibility complex (pepMHC).(B) CARs are single-chain molecules that contain a single-chain variable fragment(scFv) recognition domain capable of binding to cell surface antigens.Incomplex with each TCR are CD3 subunits andacoreceptor (CD4 orCD8) associated with Lymphocyte-specific protein tyrosine kinase (Lck).CARs contain intracellular signaling domains from CD3ζ and a co-stimulatory molecule(typically CD28 or 4-1BB).Signaling is initiated by Lck-mediated phosphorylation of immuno-tyrosine activation motifs (ITAMs) within the cytoplasmic domains of CD3.
Source: Harris D T, Kranz D M.“Adoptive T Cell Therapies: A Comparison of T Cell Receptors and Chimeric Antigen Receptors”.TrendsinPharmacolSciences, 2016, 37(3):220-230.
Chimeric antigen receptors, on the other hand, employ an antibody-antigen recognition machinery that consists of a scFv derived from an antibody in order to bind to antigens on the target cell’s surface, which, along with transmembrane domains and costimulatory domains, activates immune responses.Most proteins, however, are expressed inside cells instead of on the cell surface (only about 28% is expressed on the cell surface), making them unavailable to act as antigen for CARs.As a result, the variety of antigens that can be targeted by CARs is often limited; moreover, the densities of cell surface antigens vary from cell to cell.Traditionally, it is generally considered that CARs have higher affinity than TCRs.According to a recent study, however, by comparing between the affinity of a single-chain TCR (Vβ-linker-Vα), an analog of scFv that serves as a CAR-like receptor, and that of a CAR with the same K D, it has been shown that the full-length TCR has greater sensitivity than CAR even when CARs are expressed at higher densities and without the presence of CD8 coreceptor (which can lower the TCR affinity required by roughly 100 times and reduce the amount of pMHC required per target cell from over 30 molecules to just 1 molecule).This higher sensitivity can enable more rapid destruction of tumor cells but also increases the risk of “on-target, off-tumor” toxicity, as observed in multiple clinical trials.Interestingly, despite the higher sensitivity of TCRs than CARs, TCRs are found to mediate release of less amount of cytokines.Thus, the risk of cytokine release syndrome is potentially lower with TCR-T-cell therapy compared to CAR-T-cell therapy.Although CAR-T cells have shown promising results against hematological cancers, their efficacy for solid tumor treatments is less so, which might be due to the immunosuppressive microenvironment of solid tumors, which will be discussed in the later sections, as well as the availability of cancer antigens that are present at sufficient level of density to be targeted without “on-target, off-tumor” toxicity.T-cell receptor-engineered T cells,on the other hand, have shown some successes in treating both solid tumors, such as metastatic melanoma, and hematological cancers, possibly due to the fact that the latter is conferred with higher penetrating power due to the low number of copies present on the surface of tumors, which is contrasted by the large number of copies of CAR-T antigens[179-186].
T-cell receptor-engineered T-cell therapy utilizes the modification of T cells that retain these complexes to specifically target the antigens expressed by particular tumor cells.