HLA-DPB1 的分子差异与异基因造血干细胞移植后继发实体瘤的发生有关。
Molecular disparity of HLA-DPB1 is associated with the development of subsequent solid cancer after allogeneic hematopoietic stem cell transplantation.
机构信息
Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Division of Hematology/Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California, Irvine, California, USA.
出版信息
Cancer. 2023 Apr 15;129(8):1205-1216. doi: 10.1002/cncr.34671. Epub 2023 Feb 4.
BACKGROUND
An increased incidence of subsequent solid cancers (SSCs) has been reported in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT), and SSC is associated with inferior mortality and morbidity. Previous studies showed that the incidence of SSC is significantly higher in those who underwent allo-HSCT from HLA-mismatched donors, suggesting that persistent alloimmunity may predispose patients to SSCs. It was recently reported that, in a cohort of patients who received allo-HSCT from an unrelated donor matched at HLA-A, -B, -C, -DRB1/3/4/5, and -DQB1 loci, HLA-DPB1 alloimmunity determined by high mismatched eplets (MEs) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) score (PS), was associated with relapse protection and increased risk of acute graft-versus-host disease (GVHD).
METHODS
In the present study, the impact of HLA-DPB1 alloimmunity assessed by molecular mismatch algorithms on the development of SSCs in a cohort of 1514 patients who underwent allo-HSCT for hematologic malignancies was further investigated. ME load at the HLA-DPB1 locus was measured using the HLAMatchmaker module incorporated in HLA Fusion software, and the PS for mismatched HLA-DPB1 was calculated using the HSCT module from the PIRCHE online matching service.
RESULTS
In multivariable analysis after adjusting for baseline risk factors, higher ME, PS-I, and PS-II in the GVH direction, but not in the HVG direction, were associated with an increased risk of SSCs (ME: subdistribution hazard ratio [SHR] 1.58, p = .01; PS-I: SHR 1.59, p = .009; PS-II: SHR 1.71, p = .003). In contrast, nonpermissive HLA-DPB1 mismatches defined by the conventional T-cell epitope algorithm were not predictive of the risk of SSCs. Moreover, posttransplant cyclophosphamide-based GVHD prophylaxis was associated with a reduced risk of subsequent solid cancer (SHR 0.34, p = .021).
CONCLUSIONS
These results indicate for the first time that increased GVH alloreactivity could contribute to the development of SSCs in allo-HSCT survivors.
背景
异基因造血干细胞移植（allo-HSCT）后的继发实体瘤（SSC）发病率增加，且 SSC 与死亡率和发病率增加相关。既往研究显示，HLA 错配供者allo-HSCT 后 SSC 发病率显著更高，提示持续的同种异体免疫可能使患者易发生 SSC。最近有报道称，在一组接受 HLA-A、-B、-C、-DRB1/3/4/5 和 -DQB1 位点无关供者 allo-HSCT 的患者中，由高错配表位（ME）和预测间接可识别 HLA 表位（PIRCHE）评分（PS）确定的 HLA-DPB1 同种异体免疫与复发保护和急性移植物抗宿主病（GVHD）风险增加相关。
方法
本研究进一步探讨了通过分子错配算法评估 HLA-DPB1 同种异体免疫对 1514 例血液恶性肿瘤患者 allo-HSCT 后 SSC 发展的影响。使用 HLA 融合软件中的 HLAMatchmaker 模块测量 HLA-DPB1 位点的 ME 负荷，使用 PIRCHE 在线匹配服务的 HSCT 模块计算错配 HLA-DPB1 的 PS。
结果
在调整基线风险因素后的多变量分析中，GVH 方向而非 HVG 方向的更高 ME、PS-I 和 PS-II 与 SSCs 风险增加相关（ME：亚分布危险比[SHR]1.58，p=0.01；PS-I：SHR 1.59，p=0.009；PS-II：SHR 1.71，p=0.003）。相比之下，传统 T 细胞表位算法定义的非允许性 HLA-DPB1 错配不能预测 SSCs 的风险。此外，基于环磷酰胺的移植后 GVHD 预防与继发实体癌风险降低相关（SHR 0.34，p=0.021）。
结论
这些结果首次表明，GVH 同种异体反应性增加可能导致 allo-HSCT 幸存者 SSCs 的发生。
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