Translational control of tumor immune escape via the eIF4F–STAT1–PD-L1 axis in melanoma

Cerezo, Michaël; Guemiri, Ramdane; Druillennec, Sabine; Girault, Isabelle; Malka-Mahieu, Hélène; Shen, Shensi; Allard, Delphine; Martineau, Sylvain; Welsch, Caroline; Agoussi, Sandrine; Estrada, Charlène; Adam, Julien; Libenciuc, C.; Routier, Émilie; Roy, Séverine Le; Désaubry, Laurent; Eggermont, Alexander M.M.; Sonenberg, Nahum; Scoazec, Jean Yves; Eychène, Alain; Vagner, Stéphan; Robert, Caroline

doi:10.1038/s41591-018-0217-1

Cited by 206 publications

(178 citation statements)

References 56 publications

Supporting

Mentioning

156

Contrasting

Unclassified

Order By: Relevance

“…First, a moderate dose‐dependent reduction of STAT1 and pSTAT1 levels upon inhibition of EGFR or MEK1/2 may lower CD274 transcription (see supplementary material, Figure S3C). This might be due to inhibition of the eukaryotic initiation factor 4F (eIF4F) translation initiation complex, which is a downstream effector of the MAPK pathway and essential for cap‐dependent translation of STAT1 mRNA . Second, we observed reduced CD274 mRNA stability upon inhibition of MEK1/2 or EGFR.…”

Section: Discussionmentioning

confidence: 83%

MAPK pathway activity plays a key role in PD‐L1 expression of lung adenocarcinoma cells

Stutvoet

Kol

Vries

et al. 2019

The Journal of Pathology

132

View full text Add to dashboard Cite

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) have improved the survival of patients with non‐small cell lung cancer (NSCLC). Still, many patients do not respond to these inhibitors. PD‐L1 (CD274) expression, one of the factors that influences the efficacy of immune checkpoint inhibitors, is dynamic. Here, we studied the regulation of PD‐L1 expression in NSCLC without targetable genetic alterations in EGFR, ALK, BRAF, ROS1, MET, ERBB2 and RET. Analysis of RNA sequencing data from these NSCLCs revealed that inferred IFNγ, EGFR and MAPK signaling correlated with CD274 gene expression in lung adenocarcinoma. In a representative lung adenocarcinoma cell line panel, stimulation with EGF or IFNγ increased CD274 mRNA and PD‐L1 protein and membrane levels, which were further enhanced by combining EGF and IFNγ. Similarly, tumor cell PD‐L1 membrane levels increased after coculture with activated peripheral blood mononuclear cells. Inhibition of the MAPK pathway, using EGFR inhibitors cetuximab and erlotinib or the MEK 1 and 2 inhibitor selumetinib, prevented EGF‐ and IFNγ‐induced CD274 mRNA and PD‐L1 protein and membrane upregulation, but had no effect on IFNγ‐induced MHC‐I upregulation. Interestingly, although IFNγ increases transcriptional activity of CD274, MAPK signaling also increased stabilization of CD274 mRNA. In conclusion, MAPK pathway activity plays a key role in EGF‐ and IFNγ‐induced PD‐L1 expression in lung adenocarcinoma without targetable genetic alterations and may present a target to improve the efficacy of immunotherapy. © 2019 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

show abstract

Section: Discussionmentioning

confidence: 83%

MAPK pathway activity plays a key role in PD‐L1 expression of lung adenocarcinoma cells

Stutvoet

Kol

Vries

et al. 2019

The Journal of Pathology

132

View full text Add to dashboard Cite

show abstract

“…The former observations are in line to previous findings at the protein level, supporting an increase in the abundance levels of damage associated features (such as S100A8/A9 and HMGB2), with BC stage, 46,47 and enhance previous findings of the Lund taxonomy associating high mRNA levels of antigen presentation molecules with the most aggressive BC subtypes. 3 Of note, high levels of STAT1, EIF4A3 and EIF4G1 which are potentially controlling PD-L1 regulation based on evidence from melanoma, 48 were detected in NPS1. Along the same lines, features involved in unfolded protein response have also been previously reported as discriminatory of aggressive low grade and stage NMIBC subtypes.…”

Section: Discussionmentioning

confidence: 99%

Proteome‐based classification of Nonmuscle Invasive Bladder Cancer

Stroggilos

Mokou

Latosinska

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

DNA/RNA‐based classification of bladder cancer (BC) supports the existence of multiple molecular subtypes, while investigations at the protein level are scarce. Here, we aimed to investigate if Nonmuscle Invasive Bladder Cancer (NMIBC) can be stratified to biologically meaningful groups based on the proteome. Tissue specimens from 117 patients at primary diagnosis (98 with NMIBC and 19 with MIBC), were processed for high‐resolution proteomics analysis by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). The proteomics output was subjected to unsupervised consensus clustering, principal component analysis (PCA) and investigation of subtype‐specific features, pathways, and gene sets. NMIBC patients were optimally stratified to three NMIBC proteomic subtypes (NPS), differing in size, clinicopathologic and molecular backgrounds: NPS1 (mostly high stage/grade/risk samples) was the smallest in size (17/98) and overexpressed proteins reflective of an immune/inflammatory phenotype, involved in cell proliferation, unfolded protein response and DNA damage response, whereas NPS2 (mixed stage/grade/risk composition) presented with an infiltrated/mesenchymal profile. NPS3 was rich in luminal/differentiation markers, in line with its pathological composition (mostly low stage/grade/risk samples). PCA revealed a close proximity of NPS1 and conversely, remoteness of NPS3 to the proteome of MIBC. Proteins distinguishing these two extreme subtypes were also found to consistently differ at the mRNA levels between high and low‐risk subtypes of the UROMOL and LUND cohorts. Collectively, our study identifies three proteomic NMIBC subtypes and following a cross‐omics validation in two independent cohorts, shortlists molecular features meriting further investigation for their biomarker or potentially therapeutic value.

show abstract

“…In tumour models, silvestrol reduced STAT-1 mRNA. 17,36 Because STAT-1 is essential for DC differentiation, inhibition by silvestrol might explain the observed effects on reduced dendritic cell differentiation and activation. 41,42 Silvestrol may also modify immune cell infiltration by reducing release of chemokines and by down-regulation of adhesion molecules.…”

Section: Discussionmentioning

confidence: 99%

“…16 Such modulation of the immune system can broaden the drug efficacy profile boosting innate host defence mechanisms and thereby increasing pathogen clearance while reducing unwanted tissue damage by extenuated inflammation. Because silvestrol regulates the translation of the mRNA encoding the signal transducer and activator of transcription 1 (STAT1) transcription factor 17 that promotes innate and adaptive immune responses, 18 we speculated that silvestrol possibly interacts with the host immune system and thereby bolsters its antipathogenic effect and/or promotes resolution of inflammation and tissue damage.…”

mentioning

confidence: 99%

Natural antiviral compound silvestrol modulates human monocyte‐derived macrophages and dendritic cells

Blum

Geißlinger

Parnham

et al. 2020

J Cellular Molecular Medi

View full text Add to dashboard Cite

Over the last few years, we have had to face several severe virus-mediated disease outbreaks like the current worldwide Sars-CoV-2 pandemic, the Ebola virus outbreak in West Africa and the Zika virus outbreak in South America. The treatment options for virus-mediated diseases are limited, so well-tolerated as well as efficient antiviral therapies are urgently needed. 1 The use of the natural compound silvestrol is a promising new broad-spectrum approach for the treatment of viral infections. Silvestrol can be isolated from the plants of the genus Aglaia 2 and was initially described in the field of cancer research where it showed potent anti-tumour activity in vivo and in vitro. 3-5 The effects of silvestrol are based on the highly specific inhibition of the ATP-dependent DEAD-box RNA helicase eIF4A. 6,7 Several viruses rely on this host factor for the translation of their mRNAs. The targeting of host factors has advantages, like a Abstract Outbreaks of infections with viruses like Sars-CoV-2, Ebola virus and Zika virus lead to major global health and economic problems because of limited treatment options. Therefore, new antiviral drug candidates are urgently needed. The promising new antiviral drug candidate silvestrol effectively inhibited replication of Corona-, Ebola-, Zika-, Picorna-, Hepatis E and Chikungunya viruses. Besides a direct impact on pathogens, modulation of the host immune system provides an additional facet to antiviral drug development because suitable immune modulation can boost innate defence mechanisms against the pathogens. In the present study, silvestrol down-regulated several pro-and anti-inflammatory cytokines (IL-6, IL-8, IL-10, CCL2, CCL18) and increased TNF-α during differentiation and activation of M1-macrophages, suggesting that the effects of silvestrol might cancel each other out. However, silvestrol amplified the anti-inflammatory potential of M2-macrophages by increasing expression of anti-inflammatory surface markers CD206, TREM2 and reducing release of proinflammatory IL-8 and CCL2. The differentiation of dendritic cells in the presence of silvestrol is characterized by down-regulation of several surface markers and cytokines indicating that differentiation is impaired by silvestrol. In conclusion, silvestrol influences the inflammatory status of immune cells depending on the cell type and activation status. K E Y W O R D S antiviral, cytokines, eIF4A, energy metabolism, immune modulation, RNA viruses, rocaglate

show abstract

Translational control of tumor immune escape via the eIF4F–STAT1–PD-L1 axis in melanoma

Cited by 206 publications

References 56 publications

MAPK pathway activity plays a key role in PD‐L1 expression of lung adenocarcinoma cells

MAPK pathway activity plays a key role in PD‐L1 expression of lung adenocarcinoma cells

Proteome‐based classification of Nonmuscle Invasive Bladder Cancer

Natural antiviral compound silvestrol modulates human monocyte‐derived macrophages and dendritic cells

Contact Info

Product

Resources

About