Poster Presentation The Australasian Society for Immunology 2017 Annual Scientific Meeting

Divergent T cell receptor recognition modes of a 13-mer NY-ESO-1 tumour antigenic peptide complexed to HLA-B*07:02 (#234)

Benjamin Gully 1 2 , Kok Fei Chan 1 3 4 5 , Stephanie Gras 1 2 , Dennis Beringer 1 , Lars Kjer-Nielsen 4 , Jonathan Cebon 3 , James McCluskey 4 , Weisan Chen 3 5 , Jamie Rossjohn 1 2 6
  1. Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
  2. Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, VIC, Australia
  3. Ludwig Institute for Cancer Research, Olivia Newton-John Cancer and Wellness Centre, Austin Health, Heidelberg, VIC, Australia
  4. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC, Australia
  5. Department of Biochemistry & Genetics, La Trobe Institute of Molecular Science, La Trobe University, Bundoora, VIC, Australia
  6. Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff , United Kingdom

Human Leukocyte antigen (HLA)-I molecules generally bind short peptides (8-10 amino acids) for T cell recognition, although longer peptides (> 10 amino acids) can be presented and may comprise up to 10 % of the total HLA-I peptide repertoire.1 However, the roles of long HLA-I epitopes in tumour and viral immunity, as well as how they are subsequently recognised by T cell receptors (TCRs) remains unclear.1

Here, we describe the T cell mediated response to an immunodominant 13-amino acid peptide derived from positions 60-72 of the cancer-testis antigen, NY-ESO-1, an immunogenic antigen expressed on a range of melanomas and cancers.2 Thus, NY-ESO-1 is of significant interest due to the potential of NY-ESO-1 specific T cells as anti-cancer immunotherapeutics.3 In this study we characterised the NY-ESO-160-72-HLA-B*07:02-specific CD8+ T cell response in vaccinated HLA-B*07:02+ melanoma patients, using tetramer guided single cell sorting. Originating from this polyclonal T cell repertoire, we conducted functional analyses on NY-ESO-160-72-HLA-B*07:02 restricted T cell clones and probed the specificity and energetics of the TCR-pHLA interaction using in vitro activation assays and steady state affinity measurements. To provide a molecular basis for our findings we solved the structure of HLA-B*07:02 presenting NY-ESO-160-72 which highlighting the dynamic nature of extended peptides as presented for productive TCR engagement. We then determined the structures of two distinct TCRs bound to NY-ESO-160-72-HLA-B*07:02 in starkly differing docking modes.

Our structures highlight for the first time the extent to which TCR plasticity and polyclonality can be harnessed by the adaptive immune system to evoke an immune response against a conformational diverse epitope such as NY-ESO-160-72. Our findings provide novel insight into the recognition of extended peptide epitopes via distinct T cell populations, and highlight their utilisation of widely differing docking modes to recognise an oncogenic epitope of significant clinical interest.

  1. Rossjohn J, et al. T Cell Antigen Receptor Recognition of Antigen-Presenting Molecules. Annual Review of Immunology 33, 169-200 (2015).
  2. Ebert LM, et al. A Long, Naturally Presented Immunodominant Epitope from NY-ESO-1 Tumor Antigen: Implications for Cancer Vaccine Design. Cancer Research 69, 1046 (2009).
  3. Rapoport AP, et al. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med 21, 914-921 (2015).