Tang Xiang-Feng, Luo Yan-Hui, Si Ying-Jian, Qin Mao-Quan, Lu Wei, Chen Wei, Xing Guo-Sheng, Cao Wei, Zhou Hai-Fei, Liu Xiang-Jun
National Engineering Laboratory for Birth Defects Prevention and Control of Key Technology, Beijing Key Laboratory of Pediatric Organ Failure, Department of Pediatrics, The Seventh Medical Center of PLA General Hospital, Beijing, China.
Department of Hematology and Oncology, Beijing Children's Hospital, Capital Medical University, Beijing, China.
Front Immunol. 2025 Aug 26;16:1643244. doi: 10.3389/fimmu.2025.1643244. eCollection 2025.
Relapse continues to be a major factor contributing to therapeutic failure in haploidentical hematopoietic stem cell transplantation (HSCT). The role of natural killer (NK) cell alloreactivity mediated by killer immunoglobulin-like receptors (KIRs) is considered important in postoperative immune reconstitution and in mitigating relapse. However, its clinical implications remain incompletely defined, and its impact on allogeneic HSCT is controversial across studies.
In the present investigation, we assessed the effect of predicted NK cell alloreactivity through KIR-ligand interactions on relapse and survival outcomes in a pediatric cohort. This retrospective study included pediatric patients who underwent their first haploidentical HSCT following the Beijing protocol between 2013 and 2023. Both low- and high-resolution typing methods were employed for all donor and patient samples. The presence of NK cell alloreactivity was determined using predictive models incorporating the HLA class I molecules of both donors and recipients. NK cell alloreactivity was classified as ALLO or Non-ALLO based on the presence or absence of predicted alloreactivity, and its effects on relapse and overall survival were evaluated through individual and combinatorial interactions.
Multivariate analysis demonstrated that, among patients lacking A3/A11, those who received grafts from donors with both KIR3DL2+ and A3/A11+ had an 86% lower risk of relapse (adjusted hazard ratio 0.136; p = 0.0489). Both Synthesis-iKIR and combined Synthesis-iKIR/KIR2DS1 showed significant independent effects on overall survival, with clinically adjusted hazard ratios of 0.305 and 0.316 (p < 0.005), respectively. The disease state at transplantation was an independent clinical factor influencing prognosis. Other additive models failed to effectively predict clinical outcomes in pediatric recipients.
These results indicate that pediatric patients exhibiting NK cell alloreactivity, as predicted by the KIR3DL2-A3/A11 combination, had a significantly lower cumulative incidence of relapse. Furthermore, alloreactivity predicted by Synthesis-iKIR was significantly associated with improved overall survival. These findings have not been previously validated in pediatric studies and may have clinical relevance for haploidentical transplantation population, pending confirmation in larger cohorts.
复发仍然是导致单倍体相合造血干细胞移植（HSCT）治疗失败的主要因素。由杀伤细胞免疫球蛋白样受体（KIR）介导的自然杀伤（NK）细胞同种异体反应性在术后免疫重建和减轻复发方面的作用被认为很重要。然而，其临床意义仍未完全明确，并且在不同研究中其对异基因HSCT的影响存在争议。
在本研究中，我们评估了通过KIR-配体相互作用预测的NK细胞同种异体反应性对一组儿科患者复发和生存结局的影响。这项回顾性研究纳入了2013年至2023年间按照北京方案接受首次单倍体相合HSCT的儿科患者。对所有供体和患者样本均采用了低分辨率和高分辨率分型方法。使用包含供体和受体HLA I类分子的预测模型来确定NK细胞同种异体反应性的存在。根据预测的同种异体反应性的有无，将NK细胞同种异体反应性分为ALLO或非ALLO，并通过个体和组合相互作用评估其对复发和总生存的影响。
多变量分析表明，在缺乏A3/A11的患者中，接受来自同时具有KIR3DL2+和A3/A11+的供体移植的患者复发风险降低86%（调整后风险比0.136；p = 0.0489）。合成-iKIR和合成-iKIR/KIR2DS1联合均对总生存有显著独立影响，临床调整后的风险比分别为0.305和0.316（p < 0.005）。移植时的疾病状态是影响预后的独立临床因素。其他相加模型未能有效预测儿科受者的临床结局。
这些结果表明，如通过KIR3DL2-A3/A11组合预测的那样，表现出NK细胞同种异体反应性的儿科患者复发的累积发生率显著较低。此外，合成-iKIR预测的同种异体反应性与总生存改善显著相关。这些发现此前在儿科研究中尚未得到验证，对于单倍体相合移植人群可能具有临床相关性，有待在更大队列中得到证实。
