HLA Expression in Relation to HLA Type in Classic Hodgkin Lymphoma Patients.

Geok Wee Tan,Rianne N Veenstra,Ruth F Jarrett,Kushi Kushekhar,Ilja M Nolte,Bouke G Hepkema,Anke Van Den Berg,Arjan Diepstra,Peijia Jiang

doi:10.3390/cancers13225833

Abstract

Simple SummaryClassic Hodgkin lymphoma (cHL) is a B-cell malignancy with involvement of Epstein–Barr virus (EBV) in about 30% of the European population. The risk to develop cHL is strongly linked to genetic variants in the human leukocyte antigen (HLA) genomic region and to certain HLA alleles. This may be caused by the function of HLA alleles, or by genetic linkage to non-HLA genes. HLA can present EBV-derived and tumour-cell specific antigens and this may lead to anti-tumour immune responses. However, the tumour cells downregulate HLA expression in a proportion of the cases, which may result in immune escape. In this study, we tested whether the loss of HLA expression is related to the presence of certain protective HLA alleles. We found that loss and retention of HLA expression is indeed associated with presence of known susceptibility HLA alleles. These findings suggest that HLA itself is involved in development of cHL.Several human leukocyte antigen (HLA) alleles are strongly associated with susceptibility to classic Hodgkin lymphoma (cHL), also in subgroups stratified for presence of the Epstein–Barr virus (EBV). We tested the hypothesis that the pressure on cHL tumour cells to lose HLA expression is associated with HLA susceptibility alleles. A meta-analysis was carried out to identify consistent protective and risk HLA alleles in a combined cohort of 839 cHL patients from the Netherlands and the United Kingdom. Tumour cell HLA expression was studied in 338 cHL cases from these two cohorts and correlated to the presence of specific susceptibility HLA alleles. Carriers of the HLA-DRB1*07 protective allele frequently lost HLA class II expression in cHL overall. Patients carrying the HLA-DRB1*15/16 (DR2) risk allele retained HLA class II expression in EBV− cHL and patients with the HLA-B*37 risk allele retained HLA class I expression more frequently than non-carriers in EBV+ cHL. The other susceptibility alleles showed no significant differences in expression. Thus, HLA expression by tumour cells is associated with a subset of the protective and risk alleles. This strongly suggests that HLA associations in cHL are related to peptide binding capacities of specific HLA alleles.

Highlights

Classic Hodgkin lymphoma is a B-cell malignancy characterised by an abundant infiltrate of lymphocytes surrounding a minority of tumour cells known as Hodgkin and Reed-Sternberg (HRS) cells
Lifelong T-cell mediated immune responses restrict the number of Epstein–Barr virus (EBV) infected B-cells and prevent malignant transformation by recognition of EBV-derived antigenic peptides presented in the context of the human leukocyte antigen (HLA) [4]
HLA class I was downregulated in 72.0% (219/304) of classic Hodgkin lymphoma (cHL) cases

Summary

Introduction

Classic Hodgkin lymphoma (cHL) is a B-cell malignancy characterised by an abundant infiltrate of lymphocytes surrounding a minority of tumour cells known as Hodgkin and Reed-Sternberg (HRS) cells. Prevalence of Epstein–Barr virus (EBV) in HRS cells varies between different parts of the world, with approximately 30% of Western European cHL cases being EBV+ [2]. Lifelong T-cell mediated immune responses restrict the number of EBV infected B-cells and prevent malignant transformation by recognition of EBV-derived antigenic peptides presented in the context of the human leukocyte antigen (HLA) [4]. In ~65% of cases the HRS cells lack cell surface expression of HLA class I and this is observed most often in EBV− cHL [6]. Lack of HLA class II membranous expression is observed in ~40% of cHL cases, with a somewhat higher incidence in EBV− compared to EBV+ cHL [6,7]. In many cHL cases, HRS precursor cells most likely circumvent immune recognition by downregulating HLA expression, which prevents presentation of tumour cell derived antigenic peptides and subsequent recognition by T cells

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