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Proteogenomic discovery of neoantigens facilitates personalized multi-antigen targeted T cell immunotherapy for brain tumors
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Proteogenomic discovery of neoantigens facilitates personalized multi-antigen targeted T cell immunotherapy for brain tumors
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Journal Article
Proteogenomic discovery of neoantigens facilitates personalized multi-antigen targeted T cell immunotherapy for brain tumors
2021
Overview
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 49/23
/ 49/31
/ 82/58
/ Antigens
/ Antigens, Neoplasm - immunology
/ Brain
/ Brain Neoplasms - metabolism
/ Cerebellar Neoplasms - genetics
/ Cerebellar Neoplasms - metabolism
/ Cerebellar Neoplasms - therapy
/ Child
/ Chromatography, Liquid - methods
/ Computational Biology - methods
/ Humanities and Social Sciences
/ Humans
/ Major histocompatibility complex
/ Medulloblastoma - metabolism
/ Mutation
/ Peptides
/ Precision Medicine - methods
/ Science
/ Tumors
