UV‐induced somatic mutations elicit a functional T cell response in the YUMMER1.7 mouse melanoma model

Abstract

Summary 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 anti-tumor 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 (YUMM 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 anti-tumor immune responses.

UVB mutagenesis differs in NRAS- and BRAF-mutant mouse models of melanoma

“…Human melanoma has one of the highest mutational burdens of any tumor type 30 . Yet, tumors arising in most melanoma GEMMs, including our unirradiated TN and TB mice, are largely characterized by CNAs rather than SNVs 6,14,[24][25][26] . Here we find that a single UVB exposure can resolve this conundrum and effectively recapitulate the high burden of SNVs in human melanoma.…”

“…In contrast to human melanomas, GEMM-derived tumors are frequently characterized by a high burden of genomic copy number alterations (CNAs) and few single nucleotide variants (SNVs) 6,14,[24][25][26] . Thus, we used whole exome sequencing (WES) to determine whether a single UVA or UVB exposure would promote the formation of murine melanomas with 'humanized' cancer genomes containing a high frequency of SNVs.…”

Janus kinase inhibitor tofacitinib does not facilitate the repigmentation in mouse model of rhododendrol‐induced vitiligo

“…This strain can develop tumor immunity upon the inoculation of a small amount of human melanoma cell lines. 7 This finding suggests that T-cell response against melanocyte-specific antigens can be induced, which is relevant to the current study.…”

“…The background of mice employed in this study is C57BL/6J, which are widely used for in vivo experiments including melanoma immunotherapy. This strain can develop tumor immunity upon the inoculation of a small amount of human melanoma cell lines . This finding suggests that T‐cell response against melanocyte‐specific antigens can be induced, which is relevant to the current study.…”

Multi-model preclinical platform predicts clinical response of melanoma to immunotherapy

“…Although wildtype mice rarely develop melanomas, they have been genetically engineered with oncogenic drivers to successfully provoke melanomagenesis [23][24][25][26][27] .Nevertheless, the creation of reliable melanoma models is handicapped by the inherent differences between mouse and human skin architecture and the complexity and heterogeneity of the human disease. Moreover, the majority of genetically engineered mouse (GEM) models fail to incorporate appropriate exposure to ultraviolet (UV) radiation, known to be the major etiological melanoma risk factor and speculated to enhance susceptibility to immunotherapy 28,29 , likely contributing to the low mutation burden and poor immunogenicity that characterize most models [30][31][32]33 . These differences likely compromise the relevance and validity of current preclinical mouse studies.We have reported that constitutive activation of the receptor tyrosine kinase MET in hepatocyte growth factor transgenic mice (HGF tg ) leads to the human-like localization of melanocytes within or near the epidermis, which are then susceptible to melanoma induction by a single burning dose of neonatal UV radiation 34,35 .…”