BRAFV600E mutation correlates with suppressive tumor immune microenvironment and reduced disease-free survival in Langerhans cell histiocytosis

Abstract

Langerhans cell histiocytosis (LCH) is a neoplasm of myeloid origin characterized by a clonal proliferation of CD1a+/CD207+ dendritic cells. Recurrent BRAF V600E mutation has been reported in LCH. In the present report, we confirm the feasibility of the high-specificity monoclonal antibody VE1 for detecting BRAF V600E mutation in 36/97 (37.1%) retrospectively enrolled patients with LCH; concordant immunohistochemistry and Sanger sequencing results were seen in 94.8% of cases. We then assessed the tumor immune microenvironment status in LCH, and found that the GATA binding protein 3 (GATA3)+/T-bet+ ratio could distinguish between clinical multi-system/single-system (SS) multifocal and SS unifocal LCH. Notably, we found that BRAF V600E mutation is significantly correlated with increased programmed cell death 1 ligand 1 (PDL1) expression and forkhead box protein 3 (FOXP3)+ regulatory T cells (p < 0.001, 0.009, respectively). Moreover, Cox multivariate survival analysis showed that BRAF V600E mutation and PDL1 were independent prognostic factors of poor disease-free survival (DFS) in LCH (hazard ratio [HR] = 2.38, 95% confidence interval [CI] 1.02–5.56, p = 0.044; HR = 3.06, 95%CI 1.14–7.14, p = 0.025, respectively), and the superiority of PDL1 in sensitivity and specificity as biomarker for DFS in LCH was demonstrated by receiver operator characteristic (ROC) curves when compared with BRAF V600E and risk category. Collectively, this study identifies for the first time relationship between BRAF V600E mutation and a suppressive tumor immune microenvironment in LCH, resulting in disruption of host–tumor immune surveillance, which is DFS. Our findings may provide a rationale for combining immunotherapy and BRAF-targeted therapy for treating patients with BRAF V600E mutant LCH.

Association between clinicopathologic characteristics and BRAFV600E expression in Chinese patients with Langerhans cell histiocytosis

“…No BRAF V600E mutations were reported in adults with LCH in the study by Tong et al ., but in the studies by Wei et al . and Zeng et al ., the frequencies of BRAF V600E mutations were 17.3% and 15.6% for Chinese adult patients with LCH and 46.4% and 32% for all recruited patients with LCH, respectively. Here, we retrospectively analyzed BRAF V600E mutations and the clinical features of patients with LCH with a positive pathological diagnosis at our hospital over the last five years.…”

LRIG3 represses cell motility by inhibiting slug via inactivating ERK signaling in human colorectal cancer

“…The protocol of IHC staining was as previously described . In brief, the tissues were dewaxed and dehydrated, followed by antigen retrieval using sodium citrate buffer (pH = 6.0) and blockade by 3% H 2 O 2 and 5% bovine serum albumin.…”

“…Then, the tissues were incubated with corresponding primary and secondary antibodies, and the signal was visualized with brown DAB substrate. All sections were scored by the semi‐quantitative H‐score method, the total score is 300 …”

How I manage pulmonary Langerhans cell histiocytosis

“…Recently, a significant expression of the programmed cell death PD-1/PDL-1 immune checkpoint inhibitors and T-regulatory cells was shown to be present in the micro-environment of LCH lesions, and these markers were correlated with the presence of the BRAF V600E mutation [80][81][82].…”