title: UV-induced somatic mutations elicit a functional T cell response in the YUMMER1.7 mouse melanoma model.
abstract: Human melanomas exhibit relatively high somatic mutation burden compared to other malignancies. These somatic mutations may produce neoantigens that are recognized by the immune system, leading to an antitumor response. By irradiating a parental mouse melanoma cell line carrying three driver mutations with UVB and expanding a single-cell clone, we generated a mutagenized model that exhibits high somatic mutation burden. When inoculated at low cell numbers in immunocompetent C57BL/6J mice, YUMMER1.7 (Yale University Mouse Melanoma Exposed to Radiation) regresses after a brief period of growth. This regression phenotype is dependent on T cells as YUMMER1.7 tumors grow significantly faster in immunodeficient Rag1-/-mice and C57BL/6J mice depleted of CD4 and CD8 T cells. Interestingly, regression can be overcome by injecting higher cell numbers of YUMMER1.7, which results in tumors that grow without effective rejection. Mice that have previously rejected YUMMER1.7 tumors develop immunity against higher doses of YUMMER1.7 tumor challenge. In addition, escaping YUMMER1.7 tumors are sensitive to anti-CTLA-4 and anti-PD-1 therapy, establishing a new model for the evaluation of immune checkpoint inhibition and antitumor immune responses.
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Jake
authors.identifier: 0000-0003-2023-1861
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Curtis J
authors.initials: CJ
authors.lastname: Perry
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA.|Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Katrina
authors.initials: K
authors.lastname: Meeth
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Durga
authors.initials: D
authors.lastname: Thakral
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: William
authors.initials: W
authors.lastname: Damsky
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA.|Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Goran
authors.identifier: 0000-0003-0329-1053
authors.initials: G
authors.lastname: Micevic
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Kaech
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Blenman
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA.|Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Marcus
authors.initials: M
authors.lastname: Bosenberg
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D013601:T-Lymphocytes / Q000378:metabolism* / Q000528:radiation effects*; D014466:Ultraviolet Rays; D000073359:Exome Sequencing
chemical_list: D049452:Green Fluorescent Proteins
keywords: Braf; UV radiation; immunotherapy; melanoma; mouse models