Loss of BAP1 Is Associated with Upregulation of the NFkB Pathway and Increased HLA Class I Expression in Uveal Melanoma.

Zahra Souri,Wilma G. M. Kroes,Pieter A. van der Velden,Christiaan van Weeghel,Martine J. Jager,Annemijn P. A. Wierenga,Aart G. Jochemsen,Gregorius P. M. Luyten,Sjoerd H. van der Burg

doi:10.3390/cancers11081102

Abstract

One of the characteristics of prognostically infaust uveal melanoma (UM) is an inflammatory phenotype, which is characterized by high numbers of infiltrating T cells and macrophages, and a high HLA Class I expression. We wondered how this inflammation is regulated, and considered that one of the most important regulators of inflammation, the NFkB pathway, might play a role. We analyzed 64 UM samples for expression of HLA Class I, its regulators, and of members of the NFkB transcription family, using an Illumina HT12V4 array. HLA Class I expression and infiltrating immune cells were also determined by immunohistochemical staining. Information was obtained regarding chromosome status by Affymetrix Nsp array. Our analysis shows that expression of NFkB1, NFkB2 and RELB positively correlates with the level of HLA Class I expression and the number of infiltrating T cells and macrophages, while SPP1 and PPARγ are negatively correlated. Increased levels of NFkB1 and NFkB2 and decreased levels of SPP1 and PPARγ are seen in Monosomy 3/BAP1-negative tumors. This is also the case in non-inflammatory UM, indicating that our observation not only involves infiltrating leukocytes but the tumor cells themselves. We report that the NFkB pathway is associated with inflammation and HLA Class I expression in UM, and is upregulated when BAP1 expression is lost.

Highlights

Uveal melanoma (UM) is a malignancy that originates from melanocytes in the eye, and 50% of the patients will develop metastases [1,2]
As an increased HLA expression is one of the hallmarks of the inflammatory phenotype in UM, we wondered whether the NFkB pathway plays a role in the expression of HLA Class I (A, B) molecules
Using the three best HLA-A probes and the HLA-B probe, we determined the relation between the NFKB pathway and HLA expression in UM (Table 1)

Summary

Introduction

Uveal melanoma (UM) is a malignancy that originates from melanocytes in the eye, and 50% of the patients will develop metastases [1,2]. Secretion of inflammatory cytokines and an increase in HLA expression are frequently observed in UM, leading to an inflamed tumor environment, inside the immune-privileged eye [3]. This inflammatory phenotype is linked to an increased risk for metastasis [4,5,6,7], and has been associated with loss of chromosome 3 [8,9]. M3 occurs in almost 50% of patients and is associated with a bad prognosis [11,12,13].

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Conclusion