HLA-B44 and the Bw4-80T motif are associated with poor outcome of relapse-preventive immunotherapy in acute myeloid leukemia
HLA-B alleles are associated with outcomes in various pathologies, including autoimmune diseases and malignancies. The encoded HLA-B proteins are pivotal in antigen presentation to cytotoxic T cells, and some variants containing a Bw4 motif also serve as ligands to the killer immunoglobulin-like rec...
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Veröffentlicht in: | Cancer Immunology Immunotherapy 2023-11, Vol.72 (11), p.3559-3566 |
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Sprache: | eng |
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Zusammenfassung: | HLA-B alleles are associated with outcomes in various pathologies, including autoimmune diseases and malignancies. The encoded HLA-B proteins are 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 efficacy of immunotherapy for relapse prevention in acute myeloid leukemia (AML). Seventy-eight non-transplanted AML patients receiving HDC/IL-2 in the post-consolidation phase were genotyped for HLA-B and KIR genes. HLA-B*44 heralded impaired LFS (leukemia-free survival) and overall survival (OS), but 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 80 T-Bw4 donors showed significantly lower degranulation responses and cytokine responses than NK cells from 80I-Bw4 donors, suggesting impaired KIR3DL1-mediated education in 80 T-Bw4 subjects. We propose that presence of a strong KIR3DL1
+
–Bw4 interaction improves NK cell education and thus is advantageous in AML patients receiving HDC/IL-2 immunotherapy for relapse prevention. |
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ISSN: | 0340-7004 1432-0851 1432-0851 |
DOI: | 10.1007/s00262-023-03506-3 |