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.
Cancer. 2023 Apr 15;129(8):1205-1216. doi: 10.1002/cncr.34671. Epub 2023 Feb 4.
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).
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.
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).
These results indicate for the first time that increased GVH alloreactivity could contribute to the development of SSCs in allo-HSCT survivors.
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。
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。
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）。
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。
