BRAF V600E mutation in melanoma sustains IFN-gamma inducible PD-L1 expression by coactivating STAT1 and increasing protein translation

Wasylecka-Juszczyńska, Maja; Górniak, Patryk; Szydłowski, Maciej; Polak, Anna; Juszczyński, Przemysław

doi:10.1093/annonc/mdy289.055

Cited by 3 publications

(3 citation statements)

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“…For high frequency mutated genes of specific subtype, gene BRAF in type I encodes a protein belonging to the RAF family of serine/threonine protein kinases, which have been identified in various cancers [46]. Some research has reported that BRAF V600E mutation would sustain IFN-γ inducible PD-L1 expression by coactivating STAT1 and increasing protein translation and is associated with high levels of PD-L1 expression [47][48][49][50], and the patients with BRAF mutations appeared to benefit from monotherapy with PD-L1 inhibitors, which is consistent with results of the present study, to some extent. APC gene in type IV encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway, which was involved in other processes, including cell migration and adhesion, transcriptional activation, and apoptosis [51].…”

Section: Discussionmentioning

confidence: 99%

Multi-Omics Perspective Reveals the Different Patterns of Tumor Immune Microenvironment Based on Programmed Death Ligand 1 (PD-L1) Expression and Predictor of Responses to Immune Checkpoint Blockade across Pan-Cancer

Huang

Chen

et al. 2021

IJMS

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Immune checkpoint inhibitor (ICI) therapies have shown great promise in cancer treatment. However, the intra-heterogeneity is a major barrier to reasonably classifying the potential benefited patients. Comprehensive heterogeneity analysis is needed to solve these clinical issues. In this study, the samples from pan-cancer and independent breast cancer datasets were divided into four tumor immune microenvironment (TIME) subtypes based on tumor programmed death ligand 1 (PD-L1) expression level and tumor-infiltrating lymphocyte (TIL) state. As the combination of the TIL Z score and PD-L1 expression showed superior prediction of response to ICI in multiple data sets compared to other methods, we used the TIL Z score and PD-L1 to classify samples. Therefore, samples were divided by combined TIL Z score and PD-L1 to identify four TIME subtypes, including type I (3.24%), type II (43.24%), type III (6.76%), and type IV (46.76%). Type I was associated with favorable prognosis with more T and DC cells, while type III had the poorest condition and composed a higher level of activated mast cells. Furthermore, TIME subtypes exhibited a distinct genetic and transcriptional feature: type III was observed to have the highest mutation rate (77.92%), while co-mutations patterns were characteristic in type I, and the PD-L1 positive subgroup showed higher carbohydrates, lipids, and xenobiotics metabolism compared to others. Overall, we developed a robust method to classify TIME and analyze the divergence of prognosis, immune cell composition, genomics, and transcriptomics patterns among TIME subtypes, which potentially provides insight for classification of TIME and a referrable theoretical basis for the screening benefited groups in the ICI immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Multi-Omics Perspective Reveals the Different Patterns of Tumor Immune Microenvironment Based on Programmed Death Ligand 1 (PD-L1) Expression and Predictor of Responses to Immune Checkpoint Blockade across Pan-Cancer

Huang

Chen

et al. 2021

IJMS

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“…Effector T cell activity in the TME induces adaptive immune resistance mechanisms 46 including IFNy-mediated upregulation of immune checkpoints, including PD-L1 47 . BRAF V600 further enhances IFNy-inducible PD-L1 expression by enhancing translation via a STAT1-dependent mechanism 48 . Consistent with this, in Arm A, serum IFNy was associated with significant changes in IL-6, IL-10, and VEGF, indicative of an immunosuppressed TME.…”

Section: Discussionmentioning

confidence: 99%

Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial

Ascierto,

Casula,

Bulgarelli

et al. 2024

Nat Commun

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No prospective data were available prior to 2021 to inform selection between combination BRAF and MEK inhibition versus dual blockade of programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) as first-line treatment options for BRAFV600-mutant melanoma. SECOMBIT (NCT02631447) was a randomized, three-arm, noncomparative phase II trial in which patients were randomized to one of two sequences with immunotherapy or targeted therapy first, with a third arm in which an 8-week induction course of targeted therapy followed by a planned switch to immunotherapy was the first treatment. BRAF/MEK inhibitors were encorafenib plus binimetinib and checkpoint inhibitors ipilimumab plus nivolumab. Primary outcome of overall survival was previously reported, demonstrating improved survival with immunotherapy administered until progression and followed by BRAF/MEK inhibition. Here we report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy. We also describe preliminary results of predefined biomarkers analyses that identify a trend toward improved 4-year overall survival and total progression-free survival in patients with loss-of-function mutations affecting JAK or low baseline levels of serum interferon gamma (IFNy). These long-term survival outcomes confirm immunotherapy as the preferred first-line treatment approach for most patients with BRAFV600-mutant metastatic melanoma, and the biomarker analyses are hypothesis-generating for future investigations of predictors of durable benefit with dual checkpoint blockade and targeted therapy.

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“…Increased protein translation mediated by BRAF V600E is also not unique to LCH cells. Although BRAF V600E ‐mediated translational increases have been reported in cancers such as melanomas, 67–68 the cell‐specific consequences of increased translation have not been fully explored. Unlike melanocytes, which experience increased rates of proliferation in response to the BRAF V600E ‐mediated aberrant translation, 69 it is well established that LCH cells do not hyper‐proliferate 13,27,35,70 .…”

Section: Discussionmentioning

confidence: 99%

BRAF-V600E utilizes posttranscriptional mechanisms to amplify LPS-induced TNFα production in dendritic cells in a mouse model of Langerhans cell histiocytosis

Minichino

Chu

et al. 2022

Journal of Leukocyte Biology

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Langerhans cell histiocytosis (LCH) is an inflammatory disease characterized by abnormal dendritic cells (DCs) with hyperactive ERK signaling, called “LCH cells.” Since DCs rely on ERK signaling to produce inflammatory molecules in response to pathogenic cues, we hypothesized that hyperactive ERK enhances DCs inflammatory responses. We specifically investigated TLR4‐induced TNFα production in LCH cells by utilizing the BRAF‐V600Efl/+:CD11c‐Cre mouse model of LCH, which hyperactivates ERK in DCs. We measured LPS‐induced TNFα production both in vivo and in vitro using splenic CD11c+ cells and bone marrow‐derived DCs with or without pharmacologic BRAFV600E inhibition. We observed a reversible increase in secreted TNFα and a partially reversible increase in TNFα protein per cell, despite a decrease in TLR4 signaling and Tnfa transcripts compared with controls. We examined ERK‐driven, posttranscriptional mechanisms that contribute to TNFα production and secretion using biochemical and cellular assays. We identified a reversible increase in TACE activation, the enzyme required for TNFα secretion, and most strikingly, an increase in protein translation, including TNFα. Defining the translatome through polysome‐bound RNA sequencing revealed up‐regulated translation of the LPS‐response program. These data suggest hyperactive ERK signaling utilizes multiple posttranscriptional mechanisms to amplify inflammatory responses in DCs, advancing our understanding of LCH and basic DC biology.

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BRAF V600E mutation in melanoma sustains IFN-gamma inducible PD-L1 expression by coactivating STAT1 and increasing protein translation

Cited by 3 publications

References 0 publications

Multi-Omics Perspective Reveals the Different Patterns of Tumor Immune Microenvironment Based on Programmed Death Ligand 1 (PD-L1) Expression and Predictor of Responses to Immune Checkpoint Blockade across Pan-Cancer

Multi-Omics Perspective Reveals the Different Patterns of Tumor Immune Microenvironment Based on Programmed Death Ligand 1 (PD-L1) Expression and Predictor of Responses to Immune Checkpoint Blockade across Pan-Cancer

Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial

BRAF-V600E utilizes posttranscriptional mechanisms to amplify LPS-induced TNFα production in dendritic cells in a mouse model of Langerhans cell histiocytosis

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