Institute for Experimental Cellular Therapy, University Hospital Essen, Essen, Germany.
German Cancer Consortium, partner site Essen/Düsseldorf (DKTK), Heidelberg, Germany.
J Clin Oncol. 2023 May 1;41(13):2416-2427. doi: 10.1200/JCO.22.01229. Epub 2023 Jan 20.
Immunopeptidome divergence between mismatched HLA-DP is a determinant of T-cell alloreactivity and clinical tolerability after fully HLA-A, -B, -C, -DRB1, -DQB1 matched unrelated donor hematopoietic cell transplantation (UD-HCT). Here, we tested this concept in HLA-A, -B, and -C disparities after single class I HLA-mismatched UD-HCT.
We studied 2,391 single class I HLA-mismatched and 14,426 fully HLA-matched UD-HCT performed between 2008 and 2018 for acute leukemia or myelodysplastic syndromes. Hierarchical clustering of experimentally determined peptide-binding motifs (PBM) was used as a proxy for immunopeptidome divergence of HLA-A, -B, or -C disparities, allowing us to classify 1,629/2,391 (68.1%) of the HLA-mismatched UD-HCT as PBM-matched or PBM-mismatched. Risks associated with PBM-matching status were assessed by Cox proportional hazards models, with overall survival (OS) as the primary end point.
Relative to full matches, bidirectional or unidirectional PBM mismatches in graft-versus-host (GVH) direction (PBM-GVH mismatches, 60.7%) were associated with significantly lower OS (hazard ratio [HR], 1.48; < .0001), while unidirectional PBM mismatches in host-versus-graft direction or PBM matches (PBM-GVH matches, 39.3%) were not (HR, 1.13; = .1017). PBM-GVH mismatches also had significantly lower OS than PBM-GVH matches in direct comparison (HR, 1.32; = .0036). The hazards for transplant-related mortality and acute and chronic graft-versus-host disease but not relapse increased stepwise from full HLA matches to single PBM-GVH matches, and single PBM-GVH mismatches. A webtool for PBM-matching of single class I HLA-mismatched donor-recipient pairs was developed.
PBM-GVH mismatches inform mortality risks after single class I HLA-mismatched UD-HCT, suggesting that prospective consideration of directional PBM-matching status might improve outcome. These findings highlight immunopeptidome divergence between mismatched HLA as a driver of clinical tolerability in UD-HCT.
HLA-DP 错配导致的免疫肽组差异是完全 HLA-A、-B、-C、-DRB1、-DQB1 配型不相合无关供者造血细胞移植（UD-HCT）后 T 细胞同种异体反应性和临床耐受性的决定因素。在此，我们在 HLA-A、-B 和 -C 错配的情况下检测了单类 I HLA 错配 UD-HCT 中的这一概念。
我们研究了 2008 年至 2018 年间为急性白血病或骨髓增生异常综合征进行的 2391 例单类 I HLA 错配和 14426 例完全 HLA 配型 UD-HCT。实验确定的肽结合基序（PBM）的层次聚类被用作 HLA-A、-B 或 -C 错配免疫肽组差异的替代物，使我们能够将 2391 例 UD-HCT 中的 1629/2391（68.1%）分类为 PBM 匹配或 PBM 不匹配。通过 Cox 比例风险模型评估与 PBM 匹配状态相关的风险，以总生存（OS）为主要终点。
与完全匹配相比，移植物抗宿主病（GVH）方向的双向或单向 PBM 错配（PBM-GVH 错配，60.7%）与显著降低的 OS 相关（风险比 [HR]，1.48；<0.0001），而宿主抗移植物病方向的单向 PBM 错配或 PBM 匹配（PBM-GVH 匹配，39.3%）则没有（HR，1.13；=0.1017）。PBM-GVH 错配与直接比较中的 PBM-GVH 匹配相比，OS 也明显降低（HR，1.32；=0.0036）。从完全 HLA 匹配到单 PBM-GVH 匹配和单 PBM-GVH 错配，移植相关死亡率、急性和慢性移植物抗宿主病的风险以及复发的风险呈逐步增加。开发了一种用于单类 I HLA 错配供受者对 PBM 匹配的网络工具。
PBM-GVH 错配可预测单类 I HLA 错配 UD-HCT 后的死亡风险，提示前瞻性考虑 PBM 匹配状态可能改善结局。这些发现强调了 HLA 错配导致的免疫肽组差异是 UD-HCT 临床耐受性的驱动因素。
