Oncogene-expressing senescent melanocytes up-regulate MHC class II, a candidate melanoma suppressor function

John van Tuyn, Farah Jaber-Hijazi, Douglas MacKenzie, John J. Cole, Elizabeth Mann, Jeff S. Pawlikowski, Taranjit Singh Rai, David M. Nelson, Tony McBryan, Andre Ivanov, Karen Blyth, Hong Wu, Simon Milling, Peter D. Adams*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)
139 Downloads (Pure)

Abstract

On acquisition of an oncogenic mutation, primary human and mouse cells can enter oncogene-induced senescence (OIS). OIS is characterized by a stable proliferation arrest and secretion of pro-inflammatory cytokines and chemokines, the senescence-associated secretory phenotype (SASP). Proliferation arrest and the SASP collaborate to enact tumor suppression, the former by blocking cell proliferation and the latter by recruiting immune cells to clear damaged cells. However, the interactions of OIS cells with the immune system are still poorly defined. Here we show that engagement of OIS in primary human melanocytes, specifically by melanoma driver mutations NRASQ61K and BRAFV600E, causes expression of the MHC class II antigen presentation apparatus, via secreted IL1ß signaling and expression of CIITA, a master regulator of MHC class II gene transcription. In vitro, OIS melanocytes activate T cell proliferation. In vivo, non-proliferating, oncogene-expressing melanocytes localize to skin-draining lymph nodes where they induce T cell proliferation and an antigen presentation gene expression signature. In patients, expression of MHC class II in melanoma is linked to favorable disease outcome. We propose that OIS in melanocytes is accompanied by an antigen presentation phenotype, likely to promote tumor suppression via activation of the adaptive immune system.
Original languageEnglish
Pages (from-to)2197-2207
Number of pages11
JournalJournal of Investigative Dermatology
Volume137
Issue number10
Early online date21 Jun 2017
DOIs
Publication statusPublished - Oct 2017

Keywords

  • cellular senescence
  • antigen-expression
  • cells
  • NEVI
  • HLA
  • mutations
  • lesions
  • cancer
  • immortalization
  • fibroblasts

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