title: Neoantigen landscape dynamics during human melanoma-T cell interactions.
abstract: Recognition of neoantigens that are formed as a consequence of DNA damage is likely to form a major driving force behind the clinical activity of cancer immunotherapies such as T-cell checkpoint blockade and adoptive T-cell therapy. Therefore, strategies to selectively enhance T-cell reactivity against genetically defined neoantigens are currently under development. In mouse models, T-cell pressure can sculpt the antigenicity of tumours, resulting in the emergence of tumours that lack defined mutant antigens. However, whether the T-cell-recognized neoantigen repertoire in human cancers is constant over time is unclear. Here we analyse the stability of neoantigen-specific T-cell responses and the antigens they recognize in two patients with stage IV melanoma treated by adoptive T-cell transfer. The T-cell-recognized neoantigens can be selectively lost from the tumour cell population, either by overall reduced expression of the genes or loss of the mutant alleles. Notably, loss of expression of T-cell-recognized neoantigens was accompanied by development of neoantigen-specific T-cell reactivity in tumour-infiltrating lymphocytes. These data demonstrate the dynamic interactions between cancer cells and T cells, which suggest that T cells mediate neoantigen immunoediting, and indicate that the therapeutic induction of broad neoantigen-specific T-cell responses should be used to avoid tumour resistance.
authors.forename: Els M E
authors.initials: EM
authors.lastname: Verdegaal
authors.forename: Noel F C C
authors.initials: NF
authors.lastname: de Miranda
authors.forename: Marten
authors.initials: M
authors.lastname: Visser
authors.forename: Tom
authors.initials: T
authors.lastname: Harryvan
authors.forename: Marit M
authors.initials: MM
authors.lastname: van Buuren
authors.forename: Rikke S
authors.initials: RS
authors.lastname: Andersen
authors.forename: Sine R
authors.initials: SR
authors.lastname: Hadrup
authors.forename: Caroline E
authors.initials: CE
authors.lastname: van der Minne
authors.forename: Remko
authors.initials: R
authors.lastname: Schotte
authors.forename: Hergen
authors.initials: H
authors.lastname: Spits
authors.forename: John B A G
authors.initials: JB
authors.lastname: Haanen
authors.forename: Ellen H W
authors.initials: EH
authors.lastname: Kapiteijn
authors.forename: Ton N
authors.initials: TN
authors.lastname: Schumacher
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
mesh_terms: D019264:Adoptive Transfer; D000483:Alleles; D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D006801:Humans; D007739:L Cells; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D009154:Mutation; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019139:Tumor Escape / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte