Structural mechanisms of TCR recognition of cancer antigen pMHC

Immune surveillance plays a formidable role in eliminating cancer cells. At the centre of this process lies an interaction between the T cell receptor (TCR) in T cells and peptides presented by the major histocompatibility complex (pMHC). The biochemical and structural properties that underpin the TCR/pMHC interaction dictate the fate of infected or cancer cells. However, the rules that govern TCR specificity and sensitivity remain unknown. 

We aim to apply cryoEM and cryo-electron tomography (cryoET) including in situ structural studies to determine the structural fingerprints associated with productive TCR/pMHC interactions. We have recently made crucial technical advances in determining the structures of native unmodified TCR/pMHC complexes derived from SARS-CoV-2 infection, which had been intractable due to their intrinsic flexibility and innate low affinity. A robust cryoEM structure pipeline has thus been established for elucidating tumour-reactive TCRs in complex with natural cancer pMHCs. We will examine conserved features and differences among complexes to understand the observed specificity, sensitivity and binding affinity of TCRs recognising cancer antigens. We will also determine the complete, native TCR/CD3 and pMHC complexes from opposing membranes as they are in the immunological synapse formed between the T cell and target cancer cell using in situ cryoET.

These structures will reveal mechanisms underpinning the specificity and affinity for each TCR/pMHC pair and common shared interfaces. Such structural information will make critical contributions to the selection of TCRs for the deployment of robust and safe TCR-based immunotherapies