Specific class I HLA supertypes but not HLA zygosity or expression are associated with outcomes following HLA-matched allogeneic hematopoietic cell transplant: HLA supertypes impact allogeneic HCT outcomes

Maximizing the probability of antigen presentation to T cells through diversity in human leukocyte antigens (HLA) can enhance immune responsiveness and translate into improved clinical outcomes, as evidenced by the association of heterozygosity and supertypes at HLA class I loci with improved survival in patients with advanced solid tumors treated with immune checkpoint inhibitors. We investigated the impact of HLA heterozygosity, supertypes, and surface expression on outcomes in adult and pediatric patients with AML, MDS, ALL, and NHL who underwent 8/8 HLA-matched, T cell replete, unrelated, allogeneic hematopoietic cell transplant (HCT) from 2000 to 2015 using patient data reported to the Center for International Blood and Marrow Transplant Research. HLA class I heterozygosity and HLA expression were not associated with overall survival, relapse, transplant-related mortality (TRM), disease-free survival (DFS), and acute graft-versus-host disease following HCT. The HLA-B62 supertype was associated with decreased TRM in the entire patient cohort (HR=0.79, 95% CI 0.69 - 0.90, P=0.00053). The HLA-B27 supertype was associated with worse DFS in patients with AML (HR=1.21, 95% CI, 1.10-1.32, P=0.00005). These findings suggest that the survival benefit of HLA heterozygosity seen in solid tumor patients receiving immune checkpoint inhibition does not extend to patients undergoing allogeneic HCT. Certain HLA supertypes, however, are associated with TRM and DFS, suggesting that similarities in peptide presentation between supertype members play a role in these outcomes. Beyond implications for prognosis following HCT, these findings support the further investigation of these HLA supertypes and the specific immune peptides important for transplant outcomes.