Human leukocyte antigen-G donor-recipient matching of the 14-base pair polymorphism protects against cancer after heart transplant

Background: After a transplant, cancer is a leading cause of morbidity and mortality. Human leukocyte antigen-G (HLA-G)—an immune checkpoint molecule—reduces allograft rejection by dampening host immune responses. Reports suggest malignant cells utilize HLA-G to evade the immune system and promote cancer development. Our objective was to evaluate HLA-G donor-recipient polymorphism matching and development of cancer after a heart transplant. Methods: Recipients (n = 251) and corresponding donors (n = 196) were genotyped retrospectively to identify HLA-G polymorphisms in the 5′ regulatory (−725, −201), 3′ untranslated (+3,197, +3,187, +3,142, 14-base pair insertion-deletion polymorphism [14-bp indel]) and coding regions (Haplotypes I–VI). Associations between donor-recipient polymorphism matching and development of cancer were assessed through multivariate proportional hazard regression models. Results: Recipient and donor (48.2 ± 12.1 and 35.5 ± 14.3 years, respectively) mean follow-up was 7.2 ± 4.6 years. Overall, 42 (16.7%) recipients developed de novo post-transplant cancer. 14-bp polymorphism matching significantly reduced the proportion of cancer, revealing an independent protective effect (hazard ratio [95% CI]: 0.26 [0.10–0.75]; p = 0.012). Recipients with the 14-bp insertion sequence, whether homozygous or heterozygous, had a lower proportion of cancer (p > 0.008), matching the INS sequence (INS/INS and INS/DEL) protected against cancer (p = 0.002). No differences were seen between matched vs unmatched cohorts regarding all donor-recipient pre-transplant and post-transplant characteristics. No other polymorphisms showed significant associations. Conclusions: We investigated donor-recipient HLA-G polymorphism matching and development of cancer following a heart transplant. Donor-recipient 14-bp matching was an independent protective factor against cancer development. HLA-G may have a role in therapeutic and diagnostic strategies against cancer. Identifying relevant HLA-G polymorphisms may warrant alterations in immunotherapy to reduce post-transplant cancer risk.