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Nature. 2017 Mar 30;543(7647):723-727. doi: 10.1038/nature21433. Epub 2017 Mar 22.

Antigen presentation profiling reveals recognition of lymphoma immunoglobulin neoantigens.

Author information

1
Department of Medicine, Division of Oncology, Stanford University, Stanford, California 94305, USA.
2
Department of Chemical &Systems Biology, Stanford University, Stanford, California 94305, USA.
3
Department of Microbiology &Immunology, Stanford University, Stanford, California 94305, USA.
4
Department of Genetics, Stanford University, Stanford, California 94305, USA.
5
Department of Pathology, Stanford University, Stanford, California 94305, USA.
6
Center for Cancer Systems Biology, Stanford University, Stanford, California 94305, USA.
7
Adaptive Biotechnologies, South San Francisco, California 94080, USA.
8
Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.
9
Institute for Stem Cell Biology &Regenerative Medicine, Stanford University, Stanford, California 94305, USA.

Abstract

Cancer somatic mutations can generate neoantigens that distinguish malignant from normal cells. However, the personalized identification and validation of neoantigens remains a major challenge. Here we discover neoantigens in human mantle-cell lymphomas by using an integrated genomic and proteomic strategy that interrogates tumour antigen peptides presented by major histocompatibility complex (MHC) class I and class II molecules. We applied this approach to systematically characterize MHC ligands from 17 patients. Remarkably, all discovered neoantigenic peptides were exclusively derived from the lymphoma immunoglobulin heavy- or light-chain variable regions. Although we identified MHC presentation of private polymorphic germline alleles, no mutated peptides were recovered from non-immunoglobulin somatically mutated genes. Somatic mutations within the immunoglobulin variable region were almost exclusively presented by MHC class II. We isolated circulating CD4+ T cells specific for immunoglobulin-derived neoantigens and found these cells could mediate killing of autologous lymphoma cells. These results demonstrate that an integrative approach combining MHC isolation, peptide identification, and exome sequencing is an effective platform to uncover tumour neoantigens. Application of this strategy to human lymphoma implicates immunoglobulin neoantigens as targets for lymphoma immunotherapy.

PMID:
28329770
PMCID:
PMC5808925
DOI:
10.1038/nature21433
[Indexed for MEDLINE]
Free PMC Article

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