Abstract
MHC-bound peptides from aberrant proteins may be a specific immunotherapeutic target on cancer cells. Because of difficulties in identifying such antigens, viral or model antigens have so far been used to study their biological relevance. We here identify a naturally existing human T-cell epitope derived from a truncated protein. The antigenic peptide is derived from the gene TTK only through an alternative transcript containing a premature termination codon that may target the transcript for nonsense-mediated decay (NMD). This antigen is recognized by HLA-A*02:01-restricted CD8+ T cells derived from an allotransplanted leukemia patient. Functional analyses showed that these T cells failed to recognize several HLA-matched primary leukemic cells that expressed the alternative TTK transcript. Conventional antigen processing and presentation were not affected, suggesting that leukemic cells modify the generation of antigens processed from aberrant proteins. This natural TTK epitope provides insights in the source of transcripts producing antigenic epitopes in healthy and leukemic cells. Our data underscore potential pitfalls of targeting NMD-derived or other unconventionally generated epitopes as immunotherapeutic approach.
Highlights
The repertoire of HLA-presented peptides is dependent on antigen-containing protein expression and turnover
T cells were isolated from a patient with myelodysplastic syndrome who converted to 100% donor chimerism after treatment with allogeneic stem cell transplantation (alloSCT) and Donor lymphocyte infusion (DLI)
T cells were cultured in IMDM supplemented with 5% FBS, 5% human serum, IL2 (100 IU/mL), and restimulated every 14 days with irradiated allogeneic peripheral blood mononuclear cells (PBMC) and phytohemagglutinin (0.8 mg/mL, Murex Biotec Limited)
Summary
The repertoire of HLA-presented peptides is dependent on antigen-containing protein expression and turnover. Translational events including premature termination of translation and protein misfolding are opportunities for regulation of antigen presentation. Protein production is often elevated, which is likely to result in increased premature termination and enhanced misfolding. The rapidly degraded subset of aberrant proteins is called defective ribosomal products (DRiP). The various classes of aberrant proteins are a potential source of (neo-)antigenic peptides and may provide specific targets for T-cell–based immunotherapy [1,2,3,4].
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