title: Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing.
abstract: Human tumours typically harbour a remarkable number of somatic mutations. If presented on major histocompatibility complex class I molecules (MHCI), peptides containing these mutations could potentially be immunogenic as they should be recognized as 'non-self' neo-antigens by the adaptive immune system. Recent work has confirmed that mutant peptides can serve as T-cell epitopes. However, few mutant epitopes have been described because their discovery required the laborious screening of patient tumour-infiltrating lymphocytes for their ability to recognize antigen libraries constructed following tumour exome sequencing. We sought to simplify the discovery of immunogenic mutant peptides by characterizing their general properties. We developed an approach that combines whole-exome and transcriptome sequencing analysis with mass spectrometry to identify neo-epitopes in two widely used murine tumour models. Of the >1,300 amino acid changes identified, ∼13% were predicted to bind MHCI, a small fraction of which were confirmed by mass spectrometry. The peptides were then structurally modelled bound to MHCI. Mutations that were solvent-exposed and therefore accessible to T-cell antigen receptors were predicted to be immunogenic. Vaccination of mice confirmed the approach, with each predicted immunogenic peptide yielding therapeutically active T-cell responses. The predictions also enabled the generation of peptide-MHCI dextramers that could be used to monitor the kinetics and distribution of the anti-tumour T-cell response before and after vaccination. These findings indicate that a suitable prediction algorithm may provide an approach for the pharmacodynamic monitoring of T-cell responses as well as for the development of personalized vaccines in cancer patients.
authors.affiliation: Genentech, South San Francisco, California 94080, USA.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Yadav
authors.affiliation: Genentech, South San Francisco, California 94080, USA.
authors.forename: Suchit
authors.initials: S
authors.lastname: Jhunjhunwala
authors.affiliation: Genentech, South San Francisco, California 94080, USA.
authors.forename: Qui T
authors.initials: QT
authors.lastname: Phung
authors.affiliation: Genentech, South San Francisco, California 94080, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lupardus
authors.affiliation: Genentech, South San Francisco, California 94080, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Tanguay
authors.affiliation: Genentech, South San Francisco, California 94080, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bumbaca
authors.affiliation: Genentech, South San Francisco, California 94080, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Franci
authors.affiliation: Genentech, South San Francisco, California 94080, USA.
authors.forename: Tommy K
authors.initials: TK
authors.lastname: Cheung
authors.affiliation: Immatics Biotechnologies GmbH, 72076 Tubingen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Fritsche
authors.affiliation: Immatics Biotechnologies GmbH, 72076 Tubingen, Germany.
authors.forename: Toni
authors.initials: T
authors.lastname: Weinschenk
authors.affiliation: Genentech, South San Francisco, California 94080, USA.
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.affiliation: Genentech, South San Francisco, California 94080, USA.
authors.forename: Ira
authors.initials: I
authors.lastname: Mellman
authors.affiliation: Genentech, South San Francisco, California 94080, USA.
authors.forename: Jennie R
authors.initials: JR
authors.lastname: Lill
authors.affiliation: Genentech, South San Francisco, California 94080, USA.
authors.forename: Lélia
authors.initials: L
authors.lastname: Delamarre
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology; D045744:Cell Line, Tumor; D059472:Exome / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D007111:Immunity, Cellular / Q000276:immunology; D055261:Immunogenetic Phenomena / Q000235:genetics*; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology; D010455:Peptides / Q000235:genetics; D017434:Protein Structure, Tertiary
chemical_list: D019496:Cancer Vaccines; D010455:Peptides