TCR-T immunotherapy and cancer therapy

T-cell receptor (TCR)–engineered T-cell therapy (TCR-T) is one potentially powerful treatment that utilizes genetically modified natural T cells to specifically target tumors and destroy tumors with greater potentials [37]. Unlike CARs, TCRs rely on their interactions with peptide-major histocompatibility complex (pMHC), formed by peptide [38,39], generated from intracellular antigen proteolysis, bound with MHC (Fig. 3) [40]. Besides TCR, additional costimulatory or co-inhibitory signals are also required for TCR-T function. For example, CD4 on the surface of helper T cells, which binds to class II MHC complex, and CD8 on the surface of cytotoxic T cells, which binds to class I MHC complex, activates the TCR-T mediated cell destruction [41], while cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are responsible for T cell signaling extinguisher [42]. Given that only ~28% antigens are expressed on the cell surface, it is difficult for most of the antigens to be recognized by CAR [43]. Therefore, compared to CAR-T, TCR-T cell therapy shows remarkable advantages over the destruction of tumor cells with intracellular antigens [44]. To date, TCR-T mediated cell therapy has achieved many promising curative potency in both solid tumors and hematological cancers, and some of them have been applied in clinic trials (Table 2).

Figure 3 Diagrams of CAR-T and TCR-T-cell therapy [45]. Unlike CAR, TCR is a heterodimer containing 2 different transmembrane polypeptide chains: α chain and β chain. The α chain and β chain each consist of a constant region and a variable region, the former anchoring the chain inside the T-cell surface membrane and the latter recognizing and binding to the antigen presented by MHCs [46].

CAR-T vs TCR-T

CAR-T and TCR-T both are gene-engineered technologies targeted for the destruction of tumors by improving the recognition and destroy potentials of T cells, thus called “T cell receptor redirection” technologies. However, there are also some differences in the two technologies: 1) CAR-T recognizes their target antigen via the scFv binding domain of CAR, while TCR-T relies on the interactions with peptide-major histocompatibility complex (pMHC) and requires co-stimulatory od co-inhibitory signals; 2) CAR-T recognizes and targets cell surface antigens, while TCR-T can target both cell surface antigens and intracellular antigens; 3) CAR-T shows great therapy outcomes in the treatment of hematological cancers but little effects on solid tumors, while TCR-T displays encouraging curative outcomes in the therapy of solid tumors.

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