Oncogene-expressing senescent melanocytes upregulate MhC class II, a candidate melanoma suppressor function

van Tuyn, J. et al. (2017) Oncogene-expressing senescent melanocytes upregulate MhC class II, a candidate melanoma suppressor function. Journal of Investigative Dermatology, 137(10), pp. 2197-2207. (doi: 10.1016/j.jid.2017.05.030) (PMID:28647344) (PMCID:PMC5613751)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Jaber, Dr Farah and Ivanov, Dr Andrejs and Cole, Mr John and Blyth, Professor Karen and MacKenzie, Dr Douglas and Milling, Professor Simon and Mann, Dr Elizabeth and van Tuyn, Dr John and Nelson, Mr David and McBryan, Dr Anthony
Authors: van Tuyn, J., Jaber, F., MacKenzie, D., Cole, J. J., Mann, E., Pawlikowski, J. S., Singh Rai, T., Nelson, D. M., McBryan, T., Ivanov, A., Blyth, K., Wu, H., Milling, S., and Adams, P. D.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Investigative Dermatology
Publisher:Elsevier
ISSN:0022-202X
ISSN (Online):1523-1747
Published Online:22 June 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Journal of Investigative Dermatology 137(10): 2197-2207
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
618121The Functions of Migrating Intestinal Dendritic Cells in Tolerance and Immunity.Simon MillingMedical Research Council (MRC)MR/K021095/1III -IMMUNOLOGY
715631Defining mechanisms that control T cell migrationSimon MillingMedical Research Council (MRC)MR/N023625/1III -IMMUNOLOGY
625581Senescence-associated chromatin changes a barrier to tumor progression.Peter AdamsCancer Research UK (CRUK)16566ICS - EPIGENETICS
625582Senescence-associated chromatin changes a barrier to tumor progression.Peter AdamsCancer Research UK (CRUK)16566ICS - EPIGENETICS