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

SIMPLE SUMMARY: Classic 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. ABSTRACT: 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.