HLA-G 14BP Polymorphism Matching Protects against Development of Post-Transplant Malignancy Following Heart Transplantation

Abstract

Purpose Post-transplant malignancy (PTM) is a major cause of morbidity and mortality following transplantation. Human leukocyte antigen G (HLA-G) is an immune checkpoint molecule that reduces allograft rejection by dampening the host immune response. Reports suggest HLA-G may be utilized by malignant cells to evade the immune system and promote cancer development. Our objective was to evaluate HLA-G donor/recipient genotype matching and development of PTM following heart transplantation. Methods 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 parametric hazard regression models. Results 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 a 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 a protective factor against PTM. HLA-G may have a role in therapeutic and diagnostic strategies against cancer. Identifying relevant HLA-G polymorphisms may warrant alterations in immunotherapy in order to reduce PTM risk.