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 proinflammatory cytokines and chemokines, the senescence-associated secretory phenotype. Proliferation arrest and the senescence-associated secretory phenotype 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 major histocompatibility class II antigen presentation apparatus, via secreted IL-1ß signaling and expression of CIITA, a master regulator of major histocompatibility class II gene transcription. In vitro, OIS melanocytes activate T-cell proliferation. In vivo, nonproliferating 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 major histocompatibility 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.

Highlights

  • Melanoma is a frequently fatal cancer originating from pigment-producing melanocytes of the skin (Lo and Fisher, 2014)

  • Melanocytes express major histocompatibility (MHC) class II upon oncogene-induced senescence initiated by melanoma driver mutations As we and others previously showed (Michaloglou et al, 2005; Pawlikowski et al, 2013), ectopic expression of BRAFV600E in primary human melanocytes induces OIS

  • We previously investigated the transcriptional changes of melanocytes undergoing OIS by whole-genome microarray analysis and RNA sequencing (RNA-seq) analysis (Pawlikowski et al, 2013)

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Summary

Introduction

Melanoma is a frequently fatal cancer originating from pigment-producing melanocytes of the skin (Lo and Fisher, 2014). The most common mutations found in melanoma are those that activate the mitogen-activated protein kinase signaling pathway, most notably in BRAF and NRAS (Lo and Fisher, 2014). The same mutations are commonly found in benign nevi (or moles) (Omholt et al, 2002; Pollock et al, 2003). Benign nevi only rarely progress to cancer because oncogene-expressing nevus melanocytes are checked in a proliferation-arrested state called. Aggregates of apparently nonmalignant, nonproliferative, p16INK4aexpressing, melanocytic nevus-like cells, in the absence of any concurrent or subsequent melanoma, have been well documented in the skin-draining lymph nodes of humans (Mihic-Probst et al, 2003; Patterson, 2004)

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