Effects of epithelial to mesenchymal transition on T cell targeting of melanoma cells.

Katherine Woods,Anupama Pasam,Miles C Andrews,Jonathan Cebon,Aparna Jayachandran

doi:10.3389/fonc.2014.00367

Abstract

Melanoma cells can switch phenotype in a manner similar to epithelial to mesenchymal transition (EMT). In this perspective article, we address the effects of such phenotype switching on T cell targeting of tumor cells. During the EMT-like switch in phenotype, a concomitant change in expression of multiple tumor antigens occurs. Melanoma cells undergoing EMT escape from killing by T cells specific for antigens whose expression is downregulated by this process. We discuss melanoma antigens whose expression is influenced by EMT. We assess the effect of changes in the expressed tumor antigen repertoire on T-cell mediated tumor recognition and killing. In addition to escape from T cell immunity via changes in antigen expression, mesenchymal-like melanoma cells are generally more resistant to classical chemotherapy and radiotherapy. However, we demonstrate that when targeting antigens whose expression is unaltered during EMT, the capacity of T cells to kill melanoma cell lines in vitro is not influenced by their phenotype. When considering immune therapies such as cancer vaccination, these data suggest escape from T cell killing due to phenotype switching in melanoma could potentially be avoided by careful selection of target antigen.

Highlights

The ability of melanoma cells to switch phenotype from proliferative to more invasive states, in a process similar to classical epithelial-mesenchymal transition (EMT), has been well described [1]
We show that expression of the prototypic cancer testis antigen NY-ESO-1 is unaltered between melanoma phenotypic states
Contemporary melanoma therapy is undergoing a revolution due to the unprecedented success of immune checkpoint inhibitors; agents that re-activate anti-cancer immunity within treated patients [26]. These successes are a culmination of what scientific researchers have long striven to achieve using methods such as cancer vaccination and adoptive cell transfer, that is, appropriate immune targeting in a manner which results in tumor clearance

Summary

Introduction

The ability of melanoma cells to switch phenotype from proliferative to more invasive states, in a process similar to classical epithelial-mesenchymal transition (EMT), has been well described [1]. Included in these differentially expressed genes, were mRNAs encoding melanocytic differentiation proteins, such as Melan-A and tyrosinase Both of these have demonstrated antigenic epitopes, which have been previously used as targets of cancer vaccines in melanoma clinical trials [9,10,11], and are currently the target antigens in ongoing trials (NCT01331915, NCT01748747). Expression of these genes, as well as the master regulator of differentiation, MITF (Microphthalmia-associated transcription factor), was significantly downregulated in M-like cell lines compared to E-like [8]. A decrease in expression of the melanoma differentiation antigens (MDA) under the control of MITF during EMT has been reported by others, e.g., gp100

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Results

Conclusion