Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-26936-y
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Funding
- Common Fund of the Office of the Director of the National Institutes of Health
- NCI
- NHGRI
- NHLBI
- NIDA
- NIMH
- NINDS
- Chance for Life foundation
- Children's Cancer Foundation
- Jeff Gordon Children's Foundation
- Children's Brain Tumor Foundation
- Lilabean Foundation
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Targeting tumor-specific antigens in pediatric medulloblastomas using a proteogenomic approach may enable personalized T cell immunotherapy in these tumors with low mutational burden.
Neoantigen discovery in pediatric brain tumors is hampered by their low mutational burden and scant tissue availability. Here we develop a proteogenomic approach combining tumor DNA/RNA sequencing and mass spectrometry proteomics to identify tumor-restricted (neoantigen) peptides arising from multiple genomic aberrations to generate a highly target-specific, autologous, personalized T cell immunotherapy. Our data indicate that aberrant splice junctions are the primary source of neoantigens in medulloblastoma, a common pediatric brain tumor. Proteogenomically identified tumor-specific peptides are immunogenic and generate MHC II-based T cell responses. Moreover, polyclonal and polyfunctional T cells specific for tumor-specific peptides effectively eliminate tumor cells in vitro. Targeting tumor-specific antigens obviates the issue of central immune tolerance while potentially providing a safety margin favoring combination with other immune-activating therapies. These findings demonstrate the proteogenomic discovery of immunogenic tumor-specific peptides and lay the groundwork for personalized targeted T cell therapies for children with brain tumors. Targeting tumor-associated antigens in paediatric medulloblastomas (MB) is challenging due to their low mutational burden. Here, the authors develop a sensitive proteogenomic approach to identify tumour specific neoantigens, which may enable personalised T cell immunotherapy in paediatric MB.
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