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

Pigment Cell Melanoma Res. 2017 Jul;30(4):428-435. doi: 10.1111/pcmr.12591. Epub 2017 Jun 8.

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.

Keywords: Braf; UV radiation; immunotherapy; melanoma; mouse models.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Disease Models, Animal
  • Green Fluorescent Proteins / metabolism
  • Melanoma / genetics*
  • Melanoma / pathology*
  • Mice, Inbred C57BL
  • Mitosis / genetics
  • Mutation / genetics*
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes / radiation effects*
  • Ultraviolet Rays*
  • Whole Exome Sequencing

Substances

  • Green Fluorescent Proteins