Structural Characterization of the TIL 1383I T Cell Receptor

Abstract

Using adoptive cell transfer to reintroduce engineered T cells into patients is an exciting new form of cancer immunotherapy. T cells play a central role in adaptive immunity by eliminating virus‐infected and tumor cells. T cell receptors (TCRs) facilitate this by recognizing antigenic peptides presented by major histocompatibility complexes (MHCs), triggering an immune response. While TCRs in gene‐modified T cells can be used for anti‐tumor clinical responses, clinical trials have shown adverse effects attributable to off‐target toxicity, which stems from the inherent cross‐reactivity of a TCR repertoire developed to engage the larger universe of potential peptide antigens. To understand and begin to address this challenge in immunotherapy, elucidation of TCR structural properties and biochemical characteristics is required.TIL 1383I is a T cell receptor (TCR) that targets the human tyrosinase peptide (hTyr) overexpressed in primary and metastatic melanoma. A recent phase I clinical trial of TIL 1383I using TCR‐gene modified T cells to treat melanoma resulted in one case of durable cancer remission but other cases with partial to no responses. To help understand and possibly engineer improved variants of TIL 1383I, we recombinantly expressed TIL 1383I and crystallized it in complex with its binding partner hTyr presented by HLA‐A2. We then used X‐ray crystallography to solve the structure. The structure provides insight into the binding geometry and amino acid residues in the interface between TIL 1383I and hTyr/HLA‐A2. We have also used surface plasmon resonance to determine the TIL 1383I binding affinity. From this work, we aim to design TCR variants with the goal of improving affinity and specificity toward the hTyr antigen.Support or Funding InformationHarper Cancer Research Institute, National Institutes of Health, National Science Foundation, American Cancer SocietyThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.