BACKGROUND: Post-transplant malignancy (PTM) is a major cause of morbidity and mortality following heart transplantation. Human leukocyte antigen-G (HLA-G) is an immune checkpoint molecule which functions to dampen the immune response. HLA-G expression was initially thought to be restricted to cytotrophoblast cells, where it was shown to confer protection to the semi-allograft fetus from the maternal immune system. Since its discovery, HLA-G has been implicated as an important mediator in a variety of pathological situations, such as transplantation and cancer. Literature suggests high HLA-G expression is beneficial in reducing acute rejection by dampening the host immune response against the allograft. However, this same level of expression may be detrimental in the context of cancer; post-transplant HLA-G expression may be utilized by malignant cells as an escape mechanism to evade the host immune system and promote cancer development. Interestingly, recent evidence suggests HLA-G expression is largely mediated by genetic polymorphisms found in the gene. However, current research focuses almost entirely on recipient polymorphisms, and neglects to observe the influence of the donor genotype. Given that HLA-G may be expressed by the donor allograft, our objective was to evaluate HLA-G donor/recipient polymorphism matching and development of PTM.
METHODS AND RESULTS: Recipients (n=251) and corresponding donors (n=196) were genotyped to identify relevant HLA-G polymorphisms in the 5’regulatory region (SNP –725, –201), 3’untranslated region (SNP +3197, +3187, +3142, 14BP INDEL) and coding region (haplotypes 1-6). Diagnosis of PTM was identified via patient records. Association between donor/recipient polymorphism matching and the development of PTM was assessed with multivariate parametric hazard regression models. Recipient and donor median (IQR) age were 50(16) and 35(24) years, respectively. Mean follow-up was 7.6±4.4 years. Overall, 42 recipients had a de novo diagnosis of PTM (17%). Donor/recipient matching for the 14BP polymorphism significantly reduced the proportion of cancer, suggesting an independent protective effect (p=0.017; Figure 1). Further, the 14BP unmatched cohort had a greater number of individuals with 2 or more independent types of cancer compared to the matched group (unmatched: 8%, matched: 1%; p=0.03). No differences were seen between the 14BP matched vs. unmatched cohort regarding donor/recipient pre- and post-transplant characteristics. No other polymorphisms showed significant effects.
CONCLUSION: We investigated HLA-G polymorphism matching and the development of PTM. We identified 14BP matching as an independent protective factor against PTM. HLA-G may have a role in therapeutic/diagnostic strategies against cancer. Identifying relevant HLA-G polymorphisms may warrant alterations in immunotherapy in order to reduce PTM risk.