Prediction and effect on relapse of natural killer cell alloreactivity based on KIR-HLA interactions in pediatric haploidentical transplantation with thymoglobulin

Xiang-Feng Tang¹Yan-Hui Luo²Ying-Jian Si¹Mao-Quan Qin²Wei Lu¹Wei Chen¹Guo-Sheng Xing¹Wei Cao¹Hai-Fei Zhou^3*Xiang-Jun Liu^3*

• ¹The Seventh Medical Center of PLA General Hospital, Beijing, China
• ²Beijing Children's Hospital Capital Medical University, Beijing, China
• ³Beijing BFR Gene Diagnostics Co., Ltd, Beijing, China

Introduction 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 (KIR) is believed to be significant in postoperative immune reconstitution and in mitigating relapse; however, its clinical implications remain incompletely defined, and its impact on allogeneic HSCT is controversial across various studies. Methods In present investigation, we assessed the effect of predicted alloreactivity of NK cell through KIR-ligand interactions on relapse and survival outcomes in a pediatric cohort. This retrospective cohort study involved 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 that considered the HLA class I molecules of both the donor and recipient. NK cell alloreactivity was classified as either ALLO or Non-ALLO based on the presence or absence of predicted alloreactivity, and their effects on relapse and overall survival was evaluated through individual and combinatorial interactions. Results Multivariate analysis demonstrated that the risk of relapse for patients lacking A3/A11 who received grafts that were both KIR3DL2+ and A3/A11+ was reduced by 86% (adjusted hazard ratios 0.136, P = 0.0489). Both Synthesis-iKIR and combined Synthesis-iKIR/KIR2DS1 exhibited 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 the time of transplantation emerged as an independent clinical factor influencing prognosis. Other additive models failed to effectively predict clinical outcomes for pediatric recipients. Discussion The results indicate that patients exhibiting NK cell alloreactivity, as predicted by the KIR3DL2-A3/A11 combination, had a significantly lower cumulative incidence of relapse. Furthermore, the presence of alloreactivity predicted by Synthesis-iKIR was found to significantly enhance overall survival in pediatric patients. These findings have not been previously validated in studies involving children and may possess clinical relevance for pediatric recipients in haploidentical settings, pending confirmation in larger cohorts.