Apparent Lack of BRAFV600E Derived HLA Class I Presented Neoantigens Hampers Neoplastic Cell Targeting by CD8+ T Cells in Langerhans Cell Histiocytosis

Kemps, Paul Geraeds; Zondag, Timo; Steenwijk, Eline C.; Andriessen, Quirine; Borst, J.; Vloemans, Sandra A.; Roelen, Dave L.; Voortman, Lenard M.; Verdijk, Robert M.; Noesel, Carel J. M. van; Cleven, Arjen H.G.; Hawkins, Cynthia; Lang, Veronica; Ru, Arnoud H. de; Janssen, George M.C.; Haasnoot, Geert W.; Franken, Kees L. M. C.; Eijk, Ronald van; Solleveld‐Westerink, Nienke; Wezel, Tom van; Egeler, R. Maarten; Beishuizen, Auke; Laar, Jan A. M. van; Abla, Oussama; Bos, Cor van den; Veelen, Peter A. van; Halteren, Astrid G. S. van

doi:10.3389/fimmu.2019.03045

Cited by 6 publications

(5 citation statements)

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“…Although previous whole-exome sequencing studies have revealed infrequent additional genomic alterations in LCH, 17 , 22 , 25 several studies have indicated a distinct impact of BRAF V600E on the LCH-lesional immune microenvironment. 37 , 82 , 83 Furthermore, several studies have suggested an important role for the mutated cell-of-origin in governing LCH clinical phenotype, with high-risk disease caused by mutations in multipotent hematopoietic stem/progenitor cells and low-risk disease caused by the same mutations in more committed myeloid precursors. 16 , 84 , 85 However, this simplified model also does not fully explain LCH clinical phenotype, as recent studies have identified mutation-carrying (myeloid and lymphoid) cells in the blood from patients with low-risk or even SS LCH.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, none of the tissue samples were analyzed by BRAF VE1 immunohistochemistry alone. For (additional) molecular analysis performed in the context of this study, manual microdissection of LCH-lesional FFPE tissue sections was performed based on a CD1a-stained reference slide to obtain representative tissue parts enriched for neoplastic LCH cells, 37 thereby increasing the success rate of mutation detection. 38 Automated DNA isolation from the microdissected tissue fragments and BRAF V600E allele–specific real-time PCR and/or droplet digital PCR were performed as previously described.…”

Section: Methodsmentioning

confidence: 99%

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Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study

et al. 2023

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Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder caused by somatic genetic alterations in hematopoietic precursor cells differentiating into CD1a+/CD207+ histiocytes. LCH clinical manifestation is highly heterogeneous. BRAF and MAP2K1 mutations account for approximately 80% of genetic driver alterations in neoplastic LCH-cells. However, their clinical associations remain incompletely understood. Here, we present an international clinicogenomic study of childhood LCH, investigating 377 patients genotyped for at least BRAFV600E. MAPK pathway gene alterations were detected in 300 (79.6%) patients, including 191 (50.7%) with BRAFV600E, 54 with MAP2K1 mutations, 39 with BRAF exon 12 mutations, 13 with rare BRAF alterations, and 3 with ARAF or KRAS mutations. Our results confirm that BRAFV600E associates with lower age at diagnosis and higher prevalence of multisystem LCH, high-risk disease, and skin involvement. Furthermore, BRAFV600E appeared to correlate with a higher prevalence of central nervous system (CNS)-risk bone lesions. In contrast, MAP2K1 mutations associated with a higher prevalence of SS-bone LCH, and BRAF exon 12 deletions seemed to correlate with more lung involvement. Although BRAFV600E correlated with reduced event-free survival (EFS) in the overall cohort, neither BRAF nor MAP2K1 mutations associated with EFS when patients were stratified by disease extent. Thus, the correlation of BRAFV600E with inferior clinical outcome is (primarily) driven by its association with disease extents known for high rates of progression or relapse, including multisystem LCH. These findings advance our understanding of factors underlying the remarkable clinical heterogeneity of LCH, but also question the independent prognostic value of lesional BRAFV600E status.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study

et al. 2023

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“…The acquired data was used as starting point for the development of predictive models ranging from position-specific scoring matrices (PSSM) ( 4 ) to deep-learning approaches ( 5 ). Nevertheless, mass spectrometry remains the crucial factor for confirming presentation of peptides by HLA for a given tissue ( 6 , 7 ).…”

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confidence: 99%

Pitfalls in HLA Ligandomics—How to Catch a Li(e)gand

Fritsche

Kowalewski

Backert

et al. 2021

Molecular & Cellular Proteomics

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…However, despite the universal expression of CD40L by T cells, almost all LCH cells do not express CCR7, CD83, CD86 or lamp3 in vivo and can poorly stimulate T cells in vitro , suggesting that they represent functionally immature dendritic cells [ 71 , 80 ] . LCH cells carrying the BRAF V600E mutation are also unable to present abnormal neoantigens on human leukocyte antigen (HLA) class I molecules, which hampers their ability to stimulate CD8 + T cells and may help LCH cells avoid immune surveillance [ 81 ] . As mentioned above, the senescence phenotype and JAG2 mediated Notch activation would stimulate MMP production by LCH cells, which may contribute to tissue destruction in LCH lesions [ 46 , 65 ].…”

Section: The Pathological Function Of Histiocytes and The Inflammator...mentioning

confidence: 99%

Signaling pathways, microenvironment, and targeted treatments in Langerhans cell histiocytosis

Gao

Cao

2022

Cell Commun Signal

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Langerhans cell histiocytosis (LCH) is an inflammatory myeloid malignancy in the “L-group” histiocytosis. Mitogen-activated protein kinase (MAPK) pathway activating mutations are detectable in nearly all LCH lesions. However, the pathogenic roles of MAPK pathway activation in the development of histiocytosis are still elusive. This review will summarize research concerning the landscape and pathogenic roles of MAPK pathway mutations and related treatment opportunities in Langerhans cell histiocytosis.

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Apparent Lack of BRAFV600E Derived HLA Class I Presented Neoantigens Hampers Neoplastic Cell Targeting by CD8+ T Cells in Langerhans Cell Histiocytosis

Cited by 6 publications

References 100 publications

Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study

Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study

Pitfalls in HLA Ligandomics—How to Catch a Li(e)gand

Signaling pathways, microenvironment, and targeted treatments in Langerhans cell histiocytosis

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