RIG-I immunotherapy overcomes radioresistance in p53-positive malignant melanoma

Silke Lambing, Yu Pan Tan, Paraskevi Vasileiadou, Stefan Holdenrieder, Patrick Müller, Christian Hagen, Stephan Garbe, Rayk Behrendt, Martin Schlee, Jasper G. van den Boorn, Eva Bartok, Marcel Renn, Gunther Hartmann

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Radiotherapy induces DNA damage, resulting in cell-cycle arrest and activation of cell-intrinsic death pathways. However, the radioresistance of some tumour entities such as malignant melanoma limits its clinical application. The innate immune sensing receptor retinoic acid-inducible gene I (RIG-I) is ubiquitously expressed and upon activation triggers an immunogenic form of cell death in a variety of tumour cell types including melanoma. To date, the potential of RIG-I ligands to overcome radioresistance of tumour cells has not been investigated. Here, we demonstrate that RIG-I activation enhanced the extent and immunogenicity of irradiation-induced tumour cell death in human and murine melanoma cells in vitro and improved survival in the murine B16 melanoma model in vivo. Transcriptome analysis pointed to a central role for p53, which was confirmed using p53–/– B16 cells. In vivo, the additional effect of RIG-I in combination with irradiation on tumour growth was absent in mice carrying p53–/– B16 tumours,whiletheantitumouralresponsetoRIG-Istimulationalonewasmaintained.Ourresultsidentifyp53asapivotalcheckpoint that is triggered by RIG-I resulting in enhanced irradiation-induced tumour cell death. Thus, the combined administration of RIG-I ligands and radiotherapy is a promising approach to treating radioresistant tumours with a functional p53 pathway, such as melanoma.

Original languageEnglish
Article numbermjad001
JournalJournal of Molecular Cell Biology
Volume15
Issue number1
DOIs
StatePublished - 1 Jan 2023

Keywords

  • RIG-I
  • immunotherapy
  • irradiation
  • melanoma
  • p53
  • radioresistance
  • radiotherapy

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