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BRAF V600E 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.

journal_name

Oncoimmunology

journal_title

Oncoimmunology

authors

Zeng K,Wang Z,Ohshima K,Liu Y,Zhang W,Wang L,Fan L,Li M,Li X,Wang Y,Yu Z,Yan Q,Guo S,Wei J,Guo Y

doi

10.1080/2162402X.2016.1185582

subject

Has Abstract

pub_date

2016-06-14 00:00:00

pages

e1185582

issue

eissn

2162-4011

issn

2162-402X

pii

1185582

journal_volume

pub_type

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BRAF V600E mutation correlates with suppressive tumor immune microenvironment and reduced disease-free survival in Langerhans cell histiocytosis.