The immunopeptidome of paediatric high-grade osteosarcoma
Myrovlytis Trust
St Anna Children's Hospital
Success rates in treatment of osteosarcoma (OSA), an aggressive cancer affecting children and adolescents, have not improved over the last 30 years. High-dose, multi-agent chemotherapy followed by radical surgery has remained the standard of care. Clearly, there is an unmet need for novel, personalized therapeutic approaches. OSA tumours feature hallmarks of immune recognition in the form of tumour infiltrating lymphocytes and a gradually increasing immunosuppressive tumour microenvironment. Personalized T cell-based cancer immunotherapy may very well exploit aberrantly expressed tumour-associated antigens (TAAs) as well as somatic protein-altering mutations, which are presented as “non-self” neoantigens (NeoAgs) to T cells in the context of MHC. Current TA mining efforts rely primarily on computational pipelines to define patient-specific TAs from next generation sequencing (immunogenomics). In silico methods only incompletely recapitulate all aspects of antigen processing and presentation. As a result, predictions often fail to reflect in vivo immunogenicity. Mass spectrometry-based HLA ligandomics is the only analytical method to directly identify the HLA peptidome presented on the surface of cells or tissue in an unbiased way. Our pilot study aims to generate the first HLA ligandomics dataset for human OSA. We will test promising candidate TA peptides for immunogenicity using T cells from healthy, HLA-matched, donors. In addition to classic peptides, derived from open reading frames, we will apply a novel methodology recently developed by the Schlosser group that allows the detection of cryptic HLA peptides. Cryptic peptides represent an underappreciated class of HLA ligands, deriving from supposedly noncoding regions (“proteomic dark matter”). Current evidence suggests that certain cryptic peptides are tumour-exclusive, thus representing attractive targets for immunotherapies. By mapping the bona-fide presented HLA ligandome in a cohort of OSA patients, we aim to uncover novel, clinically relevant, T cell epitopes. Additionally, our data may reveal an OSA-specific ligandomic fingerprint, applicable across patients.
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