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Apparent Lack of BRAF(V600E) Derived HLA Class I Presented Neoantigens Hampers Neoplastic Cell Targeting by CD8(+) T Cells in Langerhans Cell Histiocytosis

Langerhans Cell Histiocytosis (LCH) is a neoplastic disorder of hematopoietic origin characterized by inflammatory lesions containing clonal histiocytes (LCH-cells) intermixed with various immune cells, including T cells. In 50–60% of LCH-patients, the somatic BRAF(V600E) driver mutation, which is c...

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Detalles Bibliográficos
Autores principales: Kemps, Paul G., Zondag, Timo C., Steenwijk, Eline C., Andriessen, Quirine, Borst, Jelske, Vloemans, Sandra, Roelen, Dave L., Voortman, Lenard M., Verdijk, Robert M., van Noesel, Carel J. M., Cleven, Arjen H. G., Hawkins, Cynthia, Lang, Veronica, de Ru, Arnoud H., Janssen, George M. C., Haasnoot, Geert W., Franken, Kees L. M. C., van Eijk, Ronald, Solleveld-Westerink, Nienke, van Wezel, Tom, Egeler, R. Maarten, Beishuizen, Auke, van Laar, Jan A. M., Abla, Oussama, van den Bos, Cor, van Veelen, Peter A., van Halteren, Astrid G. S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6967030/
https://www.ncbi.nlm.nih.gov/pubmed/31998317
http://dx.doi.org/10.3389/fimmu.2019.03045
Descripción
Sumario:Langerhans Cell Histiocytosis (LCH) is a neoplastic disorder of hematopoietic origin characterized by inflammatory lesions containing clonal histiocytes (LCH-cells) intermixed with various immune cells, including T cells. In 50–60% of LCH-patients, the somatic BRAF(V600E) driver mutation, which is common in many cancers, is detected in these LCH-cells in an otherwise quiet genomic landscape. Non-synonymous mutations like BRAF(V600E) can be a source of neoantigens capable of eliciting effective antitumor CD8(+) T cell responses. This requires neopeptides to be stably presented by Human Leukocyte Antigen (HLA) class I molecules and sufficient numbers of CD8(+) T cells at tumor sites. Here, we demonstrate substantial heterogeneity in CD8(+) T cell density in n = 101 LCH-lesions, with BRAF(V600E) mutated lesions displaying significantly lower CD8(+) T cell:CD1a(+) LCH-cell ratios (p = 0.01) than BRAF wildtype lesions. Because LCH-lesional CD8(+) T cell density had no significant impact on event-free survival, we investigated whether the intracellularly expressed BRAF(V600E) protein is degraded into neopeptides that are naturally processed and presented by cell surface HLA class I molecules. Epitope prediction tools revealed a single HLA class I binding BRAF(V600E) derived neopeptide (KIGDFGLATEK), which indeed displayed strong to intermediate binding capacity to HLA-A(*)03:01 and HLA-A(*)11:01 in an in vitro peptide-HLA binding assay. Mass spectrometry-based targeted peptidomics was used to investigate the presence of this neopeptide in HLA class I presented peptides isolated from several BRAF(V600E) expressing cell lines with various HLA genotypes. While the HLA-A(*)02:01 binding BRAF wildtype peptide KIGDFGLATV was traced in peptides isolated from all five cell lines expressing this HLA subtype, KIGDFGLATEK was not detected in the HLA class I peptidomes of two distinct BRAF(V600E) transduced cell lines with confirmed expression of HLA-A(*)03:01 or HLA-A(*)11:01. These data indicate that the in silico predicted HLA class I binding and proteasome-generated neopeptides derived from the BRAF(V600E) protein are not presented by HLA class I molecules. Given that the BRAF(V600E) mutation is highly prevalent in chemotherapy refractory LCH-patients who may qualify for immunotherapy, this study therefore questions the efficacy of immune checkpoint inhibitor therapy in LCH.