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.