High CCR6 expression increases the risk of pediatric Langerhans cell histiocytosis

Abstract

Langerhans cell histiocytosis (LCH) is a rare disorder that primarily affects children. Considering the intricate clinical presentation of this disease, the identification of specific biomarkers associated with susceptibility to LCH is essential for timely diagnosis and risk stratification. In this study, we examined the skin specimens from pediatric patients with LCH using RNAscope, immunohistochemistry, and sequencing techniques. We observed a notable correlation between elevated CCR6 expression in pathological tissues and LCH risk classification. Therefore, CCR6 expression may serve as an independent predictor of risk in clinical cases of LCH. Furthermore, the frequency of BRAF V600E mutations correlated with risk stratification. We discovered new mutations-H119Y and R108Q-in MAP2K1 in specimens with BRAF V600E mutations. Moreover, CCR6-positive tumors may exhibit an enhanced recruitment of lymphocytes expressing high CCR7 levels.

Keywords: BRAF V600E; CCR6; CCR7; Langerhans cell histiocytosis; MAP2K1.

Figure 1.

Participants section flow diagram.

Figure 2.

Clinical LCH diagnostic basis. (A) Representative image of HE staining of pathological tissue from the LCH child. (B) Representative image of immunohistochemistry (IHC) staining results of the CD1a and Langerin positivity on pathological tissue of the LCH child. (C) Representative diagram of typical structures shown by electron microscopy of pathological tissue in the LCH child. HE = hematoxylin and eosin, LCH = Langerhans cell histiocytosis.

Figure 3.

Positive correlation between CCR6 and CCR7 expression in skin tissues of children with LCH. (A) Positive correlation between CCR6 and CCR7 expression in skin tissues of children with LCH. (B) Heatmap of RNA and protein content of CCR6 and CCR7 from pathological tissues of 48 children with LCH. (C) Correlation heat map of CCR6 and CCR7 protein level in pathological tissues of 48 children with LCH. HE = hematoxylin and eosin, LCH = Langerhans cell histiocytosis.

Figure 4.

BRAF V600E mutation samples from children with LCH partially have MAP2K1 mutations. (A) Sanger sequencing shows BRAF V600E mutation. (B) Sanger sequencing shows MAP2K1 H119Y and MAP2K1 R108Q mutation. (C) MAP2K1 H119Y and MAP2K1 R108Q mutation all occurred in BRAF V600E mutant samples. (D) Statistical diagram of BRAF V600E mutation and disease progression in children with LCH. (E) Statistical plot of correlation between BRAF V600E mutation and CCR6 protein level content in children with LCH. LCH = Langerhans cell histiocytosis.