Epithelial-mesenchymal transition (EMT) signature is inversely associated with T-cell infiltration in non-small cell lung cancer (NSCLC)

Chae, Young Kwang; Chang, Sung‐Joon; Ko, Taeyeong; Anker, Jonathan F.; Agte, Sarita; Iams, Wade T.; Choi, Wooyoung M.; Lee, Kyoungmin; Cruz, Marcelo

doi:10.1038/s41598-018-21061-1

Cited by 211 publications

(209 citation statements)

References 46 publications

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“…This suggests that the diversity of immuno-editing histories depends on the tumor type. For the EMT gene set, the four immune signatures are also highly consistent in some types of tumors, such as Bladder-TCC, Lung-SCC, and Skin-Melanoma, and EMT may have important roles in the immune microenvironment in these tumors Chae et al, 2018). For the TGFβ signaling gene set, diverse associations with the four immune signatures were detected.…”

Section: Resultsmentioning

confidence: 93%

Immuno-genomic PanCancer Landscape Reveals Diverse Immune Escape Mechanisms and Immuno-Editing Histories

Mizuno

Yamaguchi

Hasegawa

et al. 2018

Preprint

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Immune reactions in the tumor micro-environment are one of the cancer hallmarks and emerging immune therapies have been proven effective in many types of cancer. To investigate cancer genomeimmune interactions and the role of immuno-editing or immune escape mechanisms in cancer development, we analyzed 2,834 whole genomes and RNA-seq datasets across 31 distinct tumor types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) project with respect to key immunogenomic aspects. We show that selective copy number changes in immune-related genes could contribute to immune escape. Furthermore, we developed an index of the immuno-editing history of each tumor sample based on the information of mutations in exonic regions and pseudogenes. Our immuno-genomic analyses of pan-cancer analyses have the potential to identify a subset of tumors with immunogenicity and diverse background or intrinsic pathways associated with their immune status and immuno-editing history.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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Section: Resultsmentioning

confidence: 93%

Immuno-genomic PanCancer Landscape Reveals Diverse Immune Escape Mechanisms and Immuno-Editing Histories

Mizuno

Yamaguchi

Hasegawa

et al. 2018

Preprint

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“…We EMT plays an important role in tumor immune escape [95][96][97] . In this context, translational control, including the MNK1/2-eIF4E axis, has been implicated in promoting an EMT across different tumor types 10,85,98,99 .…”

Section: Discussionmentioning

confidence: 99%

The MNK1/2-eIF4E axis drives melanoma plasticity, progression, and resistance to immunotherapy

Fan

Gonçalves

Bartish

et al. 2020

Preprint

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Melanomas commonly undergo a phenotype switch, from a proliferative to an invasive state. Melanoma plasticity exhibited as phenotype switching contributes to immunotherapy resistance, however the mechanisms are not completely understood and thus therapeutically unexploited. Here, using a transgenic melanoma mouse model, we demonstrated a critical role of the MNK1/2-eIF4E axis in melanoma plasticity and resistance to immunotherapy. We showed that phospho-eIF4E deficient murine melanomas express high levels of melanocytic antigens, with similar results verified in patient melanomas. Mechanistically, we identified that phospho-eIF4E controls the translation of NGFR, a critical effector of phenotype switching. In patients with melanoma, the expression of MKNK1, the kinase for eIF4E, positively correlated with markers of immune exhaustion. Genetic ablation of phospho-eIF4E reprogrammed the immunosuppressive microenvironment, exemplified by lowered production of inflammatory factors and increased CD8 + T cell infiltrates. Blocking phospho-eIF4E, using MNK1/2 inhibitors, offers a new strategy to inhibit melanoma plasticity and improve the survival response to anti-PD-1 immunotherapy.

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“…(high EMT score) the cell lines were [80]. The patient iNCCs had a score of -5, while the mother iNCCs had an EMT score of +5 and the unrelated controls had an EMT score of +8 (Fig 5D).…”

Section: Defects In the Epithelial-to-mesenchymal Transition (Emt) Inmentioning

confidence: 94%

Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells

Wood

Rowlands

Thomas

et al. 2020

Preprint

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The craniofacial developmental disorder Burn-McKeown Syndrome (BMKS) is caused by biallelic variants in the pre-messenger RNA splicing factor gene TXNL4A/DIB1. The majority of affected individuals with BMKS have a 34 base pair deletion in the promoter region of one allele of TXNL4A combined with a loss-of-function variant on the other allele, resulting in reduced TXNL4A expression. However, it is unclear how reduced expression of this ubiquitously expressed spliceosome protein results in craniofacial defects during development. Here we reprogrammed peripheral mononuclear blood cells from a BMKS patient and her unaffected mother into induced pluripotent stem cells (iPSCs) and differentiated the iPSCs into induced neural crest cells (iNCCs), the key cell type required for correct craniofacial development. BMKS patient-derived iPSCs proliferated more slowly than both mother-and unrelated control-derived iPSCs, and RNA-Seq analysis revealed significant differences in gene expression and alternative splicing. Patient iPSCs displayed defective differentiation into iNCCs compared to maternal and unrelated control iPSCs, in particular a delay in undergoing an epithelial-to-mesenchymal transition (EMT). RNA-Seq analysis of differentiated iNCCs revealed widespread gene expression changes and mis-splicing in genes relevant to craniofacial and embryonic development that highlight a dampened response to WNT signalling, the key pathway activated during iNCC differentiation. Furthermore, we identified the mis-splicing of TCF7L2 exon 4, a key gene in the WNT pathway, as a potential cause of the downregulated WNT response in patient cells. Additionally, mis-spliced genes shared common sequence properties such as length, splice site strengths and sequence motifs, suggesting that splicing of particular subsets of genes is particularly sensitive to changes in TXNL4A expression. Together, these data provide the first insight into how reduced KaryotypingKaryotyping of pluripotent iPSCs was conducted by the North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine. Apoptosis assaysCell apoptosis was assessed by annexin-V staining. For assessment of iPSCs, iPSC colonies were grown to approximately 60% confluency on VTN-treated 6-well tissue culture plates. For iNCCs, 120h differentiated iNCCs cultured on VTN-treated 6-well tissue culture plates were used. Cells were disrupted using trypsin-EDTA (Sigma) treatment and cells pelleted by centrifugation. Cells were washed once in PBS and then washed once in 1X Annexin-V Binding Buffer (ABB) (Invitrogen). The cells were resuspended at a density of 1 x 10 6 cells/ml in 1X ABB, and 7.5l APC-conjugated Annexin-V (Invitrogen) added to 100l cell suspension. The cells were incubated for 20min at room temperature in the dark, washed in 1X ABB and resuspended in 200l 1X ABB. 0.25g/ml DAPI (Invitrogen) was added and the resulting samples immediately analysed by flow cytometry. Subpopulations were ascertained in a BD LSRFortessa flow cytometer (gated using an unstained control) as f...

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Epithelial-mesenchymal transition (EMT) signature is inversely associated with T-cell infiltration in non-small cell lung cancer (NSCLC)

Cited by 211 publications

References 46 publications

Immuno-genomic PanCancer Landscape Reveals Diverse Immune Escape Mechanisms and Immuno-Editing Histories

Immuno-genomic PanCancer Landscape Reveals Diverse Immune Escape Mechanisms and Immuno-Editing Histories

The MNK1/2-eIF4E axis drives melanoma plasticity, progression, and resistance to immunotherapy

Modelling the developmental spliceosomal craniofacial disorder Burn-McKeown syndrome using induced pluripotent stem cells

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