Antigen presentation profiling reveals recognition of lymphoma immunoglobulin neoantigens.
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.
Department of Medicine, Division of Oncology, Stanford University, Stanford, California 94305, USA.
Michael S
MS
Khodadoust
Department of Chemical &Systems Biology, Stanford University, Stanford, California 94305, USA.
Niclas
N
Olsson
Department of Microbiology &Immunology, Stanford University, Stanford, California 94305, USA.
Lisa E
LE
Wagar
Department of Medicine, Division of Oncology, Stanford University, Stanford, California 94305, USA.
Ole A W
OA
Haabeth
Department of Medicine, Division of Oncology, Stanford University, Stanford, California 94305, USA.|Department of Genetics, Stanford University, Stanford, California 94305, USA.
Binbin
B
Chen
Department of Chemical &Systems Biology, Stanford University, Stanford, California 94305, USA.
Kavya
K
Swaminathan
Department of Chemical &Systems Biology, Stanford University, Stanford, California 94305, USA.
Keith
K
Rawson
Department of Medicine, Division of Oncology, Stanford University, Stanford, California 94305, USA.
Chih Long
CL
Liu
Department of Pathology, Stanford University, Stanford, California 94305, USA.
David
D
Steiner
Department of Microbiology &Immunology, Stanford University, Stanford, California 94305, USA.
Peder
P
Lund
Department of Chemical &Systems Biology, Stanford University, Stanford, California 94305, USA.
Samhita
S
Rao
Department of Chemical &Systems Biology, Stanford University, Stanford, California 94305, USA.
Lichao
L
Zhang
Department of Microbiology &Immunology, Stanford University, Stanford, California 94305, USA.
Caleb
C
Marceau
Department of Medicine, Division of Oncology, Stanford University, Stanford, California 94305, USA.
Henning
H
Stehr
Department of Medicine, Division of Oncology, Stanford University, Stanford, California 94305, USA.|Center for Cancer Systems Biology, Stanford University, Stanford, California 94305, USA.
Aaron M
AM
Newman
Department of Medicine, Division of Oncology, Stanford University, Stanford, California 94305, USA.
Debra K
DK
Czerwinski
Adaptive Biotechnologies, South San Francisco, California 94080, USA.
Victoria E H
VE
Carlton
Adaptive Biotechnologies, South San Francisco, California 94080, USA.
Martin
M
Moorhead
Adaptive Biotechnologies, South San Francisco, California 94080, USA.
Malek
M
Faham
Department of Medicine, Division of Oncology, Stanford University, Stanford, California 94305, USA.
Holbrook E
HE
Kohrt
Department of Microbiology &Immunology, Stanford University, Stanford, California 94305, USA.
Jan
J
Carette
Department of Medicine, Division of Oncology, Stanford University, Stanford, California 94305, USA.
Michael R
MR
Green
Department of Microbiology &Immunology, Stanford University, Stanford, California 94305, USA.|Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.
Mark M
MM
Davis
Department of Medicine, Division of Oncology, Stanford University, Stanford, California 94305, USA.
Ronald
R
Levy
Department of Chemical &Systems Biology, Stanford University, Stanford, California 94305, USA.
Joshua E
JE
Elias
Department of Medicine, Division of Oncology, Stanford University, Stanford, California 94305, USA.|Center for Cancer Systems Biology, Stanford University, Stanford, California 94305, USA.|Institute for Stem Cell Biology &Regenerative Medicine, Stanford University, Stanford, California 94305, USA.
Ash A
AA
Alizadeh
D017951:Antigen Presentation / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004252:DNA Mutational Analysis; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D059472:Exome / Q000235:genetics; D023281:Genomics; D006681:HLA-D Antigens / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D007167:Immunotherapy / Q000639:trends; D020522:Lymphoma, Mantle-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D009154:Mutation; D040901:Proteomics
D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D006681:HLA-D Antigens; D015395:Histocompatibility Antigens Class I; D007135:Immunoglobulin Variable Region