Antigen presentation profiling reveals recognition of lymphoma immunoglobulin neoantigens

Michael S. Khodadoust, Niclas Olsson, Lisa E. Wagar, Ole A.W. Haabeth, Binbin Chen, Kavya Swaminathan, Keith Rawson, Chih Long Liu, David Steiner, Peder Lund, Samhita Rao, Lichao Zhang, Caleb Marceau, Henning Stehr, Aaron M. Newman, Debra K. Czerwinski, Victoria E.H. Carlton, Martin Moorhead, Malek Faham, Holbrook E. KohrtJan Carette, Michael R. Green, Mark M. Davis, Ronald Levy, Joshua E. Elias, Ash A. Alizadeh

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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.

Original languageEnglish (US)
Pages (from-to)723-727
Number of pages5
JournalNature
Volume543
Issue number7647
DOIs
StatePublished - Mar 30 2017

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Cite this

Khodadoust, M. S., Olsson, N., Wagar, L. E., Haabeth, O. A. W., Chen, B., Swaminathan, K., Rawson, K., Liu, C. L., Steiner, D., Lund, P., Rao, S., Zhang, L., Marceau, C., Stehr, H., Newman, A. M., Czerwinski, D. K., Carlton, V. E. H., Moorhead, M., Faham, M., ... Alizadeh, A. A. (2017). Antigen presentation profiling reveals recognition of lymphoma immunoglobulin neoantigens. Nature, 543(7647), 723-727. https://doi.org/10.1038/nature21433