4.Discussion
This study investigated the association of sCD25 levels with the clinical characteristics and prognosis of pediatric LCH and demonstrated that the higher levels of sCD25 were associated with the high-risk features and inferior outcome of LCH.
LCH comprises qualities of both neoplasia and immunogenic components, and inflammation also plays a vital role in the pathophysiology of LCH33-35. LCH lesions are accompanied by a diverse inflammatory infiltrate, enriching dysfunctional T cells36-38. The IL-2 pathway plays a crucial role in regulating the immune response, and sCD25, a component of the IL-2 receptor, is shed during immune activation that serves as a marker of T cell activation39-42. Elevated sCD25 was previously reported in LCH patients before treatment and correlated with disease extent23,24,43. Our finding showed that sCD25 levels were significantly higher in patients with multisystem disease and RO involvements, in agreement with the above reports. Moreover, we demonstrated that the higher sCD25 levels at baseline were closely associated with other high-risk features, including young age and involvements of skin, lung, or lymph nodes. Increased sCD25 also correlated with the positivity of cfBRAF -V600E in plasma, which has been proved to relate to inferior prognosis. Notably, our data showed remarkably elevated sCD25 levels in LCH patients with MAS-HLH, which is a fatal presentation char3acterized by the over-activation of T cells and macrophages that excessively produce inflammatory cytokines, cytopenias, hepatosplenomegaly and many other manifestations44. sCD25 is mainly produced by activated T cells, indicating up-regulated levels of sCD25 in LCH patients who had activated T cell proliferation.
Moreover, our results revealed apparently decreased plasma sCD25 after dabrafenib administration or chemotherapy, suggesting sCD25 was released by pathological cells that carried the BRAF -V600E driver mutation. Previous studies have mentioned that sCD25 can be used to monitor disease activity and treatment response. In LCH patients who responded to the induction therapy, serum levels of sCD25 decreased significantly after the chemotherapy23. However, the exact relationship between changes in CD25 levels and response to treatment has not been clarified, due to the rarity and heterogeneity of the LCH disease. Therefore, prospective cohorts need to be established and CD25 levels should be monitored at multiple time points during chemotherapy and targeted treatment to further explore the correlation between CD25 and treatment response.
Advances in risk-stratified treatment and the application of targeted therapies have led to a significant improvement in overall survival of LCH patients, but refractory or recurrent diseases remain a major obstacle to the further improvement of prognosis, with approximately one-third of patients relapsing after discontinuation of therapy27,45. The present study demonstrates that the high sCD25 levels at diagnosis independently predicted inferior PFS in patients receiving first-line chemotherapy, presenting cut-off values, sensitivity, specificity, and accuracy. sCD25 levels ≥ 2921 pg/ml were found to have an independent predictive impact (hazard ratio: 2.577) in the test cohort, which was confirmed in the independent validation cohort. Due to inter-laboratory deviations, the optimal cut-off for sCD25 varied among different laboratories based on individual laboratory reference values. In particular, measurements should be standardized to minimize inter-laboratory variability.