Interpreting T-Cell Cross-reactivity through Structure: Implications for TCR-Based Cancer Immunotherapy

Abstract

Immunotherapy has become one of the most promising avenues for cancer treatment, making use of the patient’s own immune system to eliminate cancer cells. Clinical trials with T-cell-based immunotherapies have shown dramatic tumor regressions, being effective in multiple cancer types and for many different patients. Unfortunately, this progress was tempered by reports of serious (even fatal) side effects. Such therapies rely on the use of cytotoxic T-cell lymphocytes, an essential part of the adaptive immune system. Cytotoxic T-cells are regularly involved in surveillance and are capable of both eliminating diseased cells and generating protective immunological memory. The specificity of a given T-cell is determined through the structural interaction between the T-cell receptor (TCR) and a peptide-loaded major histocompatibility complex (MHC); i.e., an intracellular peptide–ligand displayed at the cell surface by an MHC molecule. However, a given TCR can recognize different peptide–MHC (pMHC) complexes, which can sometimes trigger an unwanted response that is referred to as T-cell cross-reactivity. This has become a major safety issue in TCR-based immunotherapies, following reports of melanoma-specific T-cells causing cytotoxic damage to healthy tissues (e.g., heart and nervous system). T-cell cross-reactivity has been extensively studied in the context of viral immunology and tissue transplantation. Growing evidence suggests that it is largely driven by structural similarities of seemingly unrelated pMHC complexes. Here, we review recent reports about the existence of pMHC “hot-spots” for cross-reactivity and propose the existence of a TCR interaction profile (i.e., a refinement of a more general TCR footprint in which some amino acid residues are more important than others in triggering T-cell cross-reactivity). We also make use of available structural data and pMHC models to interpret previously reported cross-reactivity patterns among virus-derived peptides. Our study provides further evidence that structural analyses of pMHC complexes can be used to assess the intrinsic likelihood of cross-reactivity among peptide-targets. Furthermore, we hypothesize that some apparent inconsistencies in reported cross-reactivities, such as a preferential directionality, might also be driven by particular structural features of the targeted pMHC complex. Finally, we explain why TCR-based immunotherapy provides a special context in which meaningful T-cell cross-reactivity predictions can be made.

Epstein-Barr Virus Epitope–Major Histocompatibility Complex Interaction Combined with Convergent Recombination Drives Selection of Diverse T Cell Receptor α and β Repertoires

“…TCR cloning and site-directed mutagenesis of the CDR3␣ lysine ablated EBV-BR-tetramer staining and function. Interestingly, we had previously used TCR structural modeling of the EBV-YVL-BR/MHC complex to predict the occurrence of this important protuberant lysine which might impact TCR interaction (64). Future structural analyses will be important to ascertain whether the YVL-BR TCR␣ contributes the majority of contacts with the pMHC.…”

High diversity, turnover, and structural constraints characterize TCR α and β repertoire selection

“…In a recent study comparing TCRα/β repertoires of various human and murine viral epitopes, none of the responses were primarily driven by interaction with TCRα alone; rather they were predominantly driven by strong interactions with TCRβ or a combination of TCRα/β 9 . Our YVL/MHC crystal structure data ( Fig 6E) and structural modeling data 42 49 and against skewing of the response after infection with a cross-reactive pathogen 50,51 . The large number of clonotypes contributes to the overall memory T-cell pool, enhancing the opportunity for protective heterologous immunity now recognized to be an important aspect of immune maturation 52 .…”

Epstein Barr virus epitope/MHC interaction combined with convergent recombination drive selection of diverse T cell receptor α and β repertoires

“…TCR cloning and site-directed mutagenesis of the CDR3α lysine ablated EBV-BR-tetramer staining and function. Interestingly, we had previously used TCR structural modeling of the EBV-YVL-BR/MHC complex to predict the occurrence of this important protuberant lysine which might impact TCR interaction (64). Future structural analyses would be important to ascertain whether the YVL-BR TCRα contributes the majority of contacts with the pMHC.…”