HLA-B*44 and the Bw4-80T motif are associated with poor outcome of relapse-preventive immunotherapy in acute myeloid leukemia

Abstract

HLA-B proteins interact with key immune receptors on both T and NK cells, and variants of the encoding gene are associated with outcomes in various pathologies, including autoimmune diseases and malignancies. HLA-B is pivotal in antigen presentation to cytotoxic T cells, and some variants containing a Bw4 motif also serve as ligands to the killer immunoglobulin-like receptors (KIR) 3DL1/S1 of NK cells. We investigated the potential impact of HLA-B genotypes on the efficiency of immunotherapy for relapse prevention in acute myeloid leukemia (AML). Seventy-nine non-transplanted AML patients receiving HDC/IL-2 in the post-consolidation phase were genotyped for HLA-B and KIRs genes. HLA-B*07 associated with improved leukemia-free survival (LFS), while HLA-B*44 heralded impaired LFS and overall survival (OS). The negative association with outcome was not shared across alleles of the HLA-B44 supertype. Notably, HLA-B*44 is one of few HLA-B44 supertype alleles containing a Bw4 motif with a threonine at position 80, which typically results in weak binding to the inhibitory NK receptor, KIR3DL1. Accordingly, a strong interaction between KIR3DL1 and Bw4 was associated with superior LFS and OS (p = 0.014 and p = 0.027, respectively). KIR3DL1+ NK cells from 80T-Bw4 donors showed significantly lower degranulation responses and cytokine responses than NK cells from 80I-Bw4 donors, suggesting impaired KIR3DL1-mediated education in 80T-Bw4 subjects. We propose that presence of a strong KIR3DL1+ - Bw4 interaction is advantageous in AML patients receiving immunotherapy for relapse prevention. This is likely achieved by improved NK cell education and a reduced expression of HLA-Bw4 on malignant leukemic cells.