Cancer Cell Phenotype Plasticity as a Driver of Immune Escape in Melanoma

Benboubker, Valentin; Boivin, Félix; Dalle, Stéphane; Caramel, Julie

doi:10.3389/fimmu.2022.873116

Cited by 17 publications

(14 citation statements)

References 148 publications

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“…TNF and TGF mimic only part of the signals emanating from the tumor microenvironment. Indeed, we recently highlighted the major crosstalk existing between melanoma cells and their immune microenvironment (38,42) and recent work from the Marine lab highlighted the major role of endothelial cells in promoting a mesenchymal state (43). ZEB1…”

Section: Discussionmentioning

confidence: 99%

“…TNFα and TGFβ mimic only part of the signals emanating from the tumor microenvironment. Indeed, we recently highlighted the major crosstalk existing between melanoma cells and their immune microenvironment (38,42) and recent work from the Marine lab highlighted the major role of endothelial cells in promoting a mesenchymal state (43). ZEB1 and other melanoma markers of intra-tumor heterogeneity may thus significantly be modified by the tumor microenvironment in specific niches that will deserve further characterization.…”

Section: Discussionmentioning

confidence: 99%

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ZEB1 controls a lineage-specific transcriptional program essential for melanoma cell state transitions

Tang

Durand

Pommier

et al. 2023

Preprint

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Cell plasticity sustains intra-tumor heterogeneity and treatment resistance in melanoma. Deciphering the transcriptional mechanisms governing reversible phenotypic transitions between proliferative/differentiated and invasive/stem-like states is required in order to design novel therapeutic strategies. EMT-inducing transcription factors, extensively known for their role in metastasis in carcinoma, display cell-type specific functions in melanoma, with a decreased ZEB2/ZEB1 expression ratio fostering adaptive resistance to targeted therapies. While ZEB1 direct target genes have been well characterized in carcinoma models, they remain unknown in melanoma. Here, we performed a genome-wide characterization of ZEB1 transcriptional targets, by combining ChIP-sequencing and RNA-sequencing, upon phenotype switching in melanoma models. We identified and validated ZEB1 binding peaks in the promoter of key lineage-specific genes related to melanoma cell identity. Comparative analyses with breast carcinoma cells demonstrated melanoma-specific ZEB1 binding, further supporting lineage specificity. Gain- or loss-of-function of ZEB1, combined with functional analyses, further demonstrated that ZEB1 negatively regulates proliferative/melanocytic programs and positively regulates both invasive and stem-like programs. We then developed single-cell spatial multiplexed analyses to characterize melanoma cell states with respect to ZEB1/ZEB2 expression in human melanoma samples. We characterized the intra-tumoral heterogeneity of ZEB1 and ZEB2 and further validated ZEB1 increased expression in invasive cells, but also in stem-like cells, highlighting its relevance in vivo in both populations. Overall, our results define ZEB1 as a major transcriptional regulator of cell states transitions and provide a better understanding of lineage-specific transcriptional programs sustaining intra-tumor heterogeneity in melanoma.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

ZEB1 controls a lineage-specific transcriptional program essential for melanoma cell state transitions

Tang

Durand

Pommier

et al. 2023

Preprint

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“…Whereas sustained responses may be observed with anti-PD-1 antibody therapy, around 60% of patients still develop resistance ( 12 , 21 ). Cancer cell phenotype plasticity ( 22 , 23 ), tumor microenvironment ( 24 ), the expression of immune checkpoint genes ( 25 ) and other factors may be related to immune escape in melanoma. What’s more, the reported genomic and immune biomarkers are not accurate enough in evaluating therapeutic effects ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

A CD8+ T cell-associated immune gene panel for prediction of the prognosis and immunotherapeutic effect of melanoma

Sun

Zhi²,

Su³

et al. 2022

Front. Immunol.

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BackgroundSkin cutaneous melanoma (SKCM) is the most frequently encountered tumor of the skin. Immunotherapy has opened a new horizon in melanoma treatment. We aimed to construct a CD8+ T cell-associated immune gene prognostic model (CDIGPM) for SKCM and unravel the immunologic features and the benefits of immunotherapy in CDIGPM-defined SKCM groups.MethodSingle-cell SKCM transcriptomes were utilized in conjunction with immune genes for the screening of CD8+ T cell-associated immune genes (CDIGs) for succeeding assessment. Thereafter, through protein-protein interaction (PPI) networks analysis, univariate COX analysis, and multivariate Cox analysis, six genes (MX1, RSAD2, IRF2, GBP2, IFITM1, and OAS2) were identified to construct a CDIGPM. We detected cell proliferation of SKCM cells transfected with IRF2 siRNA. Then, we analyzed the immunologic features and the benefits of immunotherapy in CDIGPM-defined groups.ResultsThe overall survival (OS) was much better in low-CDIGPM group versus high CDIGPM group in TCGA dataset and GSE65904 dataset. On the whole, the results unfolded that a low CDIGPM showed relevance to immune response-correlated pathways, high expressions of CTLA4 and PD-L1, a high infiltration rate of CD8+ T cells, and more benefits from immunotherapy.ConclusionCDIGPM is an good model to predict the prognosis, the potential immune escape from immunotherapy for SKCM, and define immunologic and molecular features.

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“…CSCs and EMT share a high degree of consistency and may be a partially overlapping concept. 86,87 As mentioned, the EMT program largely facilitates tumor cell dissemination. CSCs are also enriched in disseminated tumor cells and feature EMT expression signatures.…”

Section: Cancer Stem Cellsmentioning

confidence: 97%

Tumor cell plasticity in targeted therapy-induced resistance: mechanisms and new strategies

Pang

Yang

et al. 2023

Sig Transduct Target Ther

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Despite the success of targeted therapies in cancer treatment, therapy-induced resistance remains a major obstacle to a complete cure. Tumor cells evade treatments and relapse via phenotypic switching driven by intrinsic or induced cell plasticity. Several reversible mechanisms have been proposed to circumvent tumor cell plasticity, including epigenetic modifications, regulation of transcription factors, activation or suppression of key signaling pathways, as well as modification of the tumor environment. Epithelial-to-mesenchymal transition, tumor cell and cancer stem cell formation also serve as roads towards tumor cell plasticity. Corresponding treatment strategies have recently been developed that either target plasticity-related mechanisms or employ combination treatments. In this review, we delineate the formation of tumor cell plasticity and its manipulation of tumor evasion from targeted therapy. We discuss the non-genetic mechanisms of targeted drug-induced tumor cell plasticity in various types of tumors and provide insights into the contribution of tumor cell plasticity to acquired drug resistance. New therapeutic strategies such as inhibition or reversal of tumor cell plasticity are also presented. We also discuss the multitude of clinical trials that are ongoing worldwide with the intention of improving clinical outcomes. These advances provide a direction for developing novel therapeutic strategies and combination therapy regimens that target tumor cell plasticity.

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Cancer Cell Phenotype Plasticity as a Driver of Immune Escape in Melanoma

Cited by 17 publications

References 148 publications

ZEB1 controls a lineage-specific transcriptional program essential for melanoma cell state transitions

ZEB1 controls a lineage-specific transcriptional program essential for melanoma cell state transitions

A CD8+ T cell-associated immune gene panel for prediction of the prognosis and immunotherapeutic effect of melanoma

Tumor cell plasticity in targeted therapy-induced resistance: mechanisms and new strategies

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