Zeb1 induces immune checkpoints to form an immunosuppressive envelope around invading cancer cells

Guo, Yan; Lu, Xiaoqin; Chen, Yao; Rendon, Beatriz E.; Mitchell, Robert A.; Cuatrecasas, Míriam; Cortés, Marlies; Postigo, Antonio; Liu, Yongqing; Dean, Douglas C.

doi:10.1126/sciadv.abd7455

Cited by 61 publications

(32 citation statements)

References 62 publications

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“…In cancer cells, a multitude of molecular players modulate PD-L1 levels at various regulatory stages (2). Of interest here is the finding that PD-L1 levels can be increased as cells go through an Epithelial-Mesenchymal Transition (EMT) and consequently gain the ability to migrate and invade (4)(5)(6)(7)(8)(9)(10)(11)(12)(13), as noted in in vitro models as well as in patient samples across cancer types. It is, however, important to note here that tumours from metastatic sites have often been shown to have relatively low levels of PD-L1 (14,15).…”

Section: Introductionmentioning

confidence: 99%

Immunosuppressive Traits of the Hybrid Epithelial/Mesenchymal Phenotype

et al. 2021

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Recent preclinical and clinical data suggests enhanced metastatic fitness of hybrid epithelial/mesenchymal (E/M) phenotypes, but mechanistic details regarding their survival strategies during metastasis remain unclear. Here, we investigate immune-evasive strategies of hybrid E/M states. We construct and simulate the dynamics of a minimalistic regulatory network encompassing the known associations among regulators of EMT (epithelial-mesenchymal transition) and PD-L1, an established immune-suppressor. Our simulations for the network consisting of SLUG, ZEB1, miR-200, CDH1 and PD-L1, integrated with single-cell and bulk RNA-seq data analysis, elucidate that hybrid E/M cells can have high levels of PD-L1, similar to those seen in cells with a full EMT phenotype, thus obviating the need for cancer cells to undergo a full EMT to be immune-evasive. Specifically, in breast cancer, we show the co-existence of hybrid E/M phenotypes, enhanced resistance to anti-estrogen therapy and increased PD-L1 levels. Our results underscore how the emergent dynamics of interconnected regulatory networks can coordinate different axes of cellular fitness during metastasis.

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Section: Introductionmentioning

confidence: 99%

Immunosuppressive Traits of the Hybrid Epithelial/Mesenchymal Phenotype

et al. 2021

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“…Notably, the EMT-TF ZEB1 was shown to stimulate PD-L1 expression by repressing miR-200 in lung and breast cancer, leading to immune escape and metastasis (101,102). Consistently, spontaneous lung tumors in mice with inactivated Zeb1 harbor a significantly reduced PD-L1 expression at the invasive front, associated with a stronger anti-tumor immunity in this model (103).…”

Section: Resistance To Lysis Upregulated Pd-l1 Expressionmentioning

confidence: 54%

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

et al. 2022

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Immunotherapies blocking negative immune checkpoints are now approved for the treatment of a growing number of cancers. However, even in metastatic melanoma, where sustained responses are observed, a significant number of patients still do not respond or display resistance. Increasing evidence indicates that non-genetic cancer cell-intrinsic alterations play a key role in resistance to therapies and immune evasion. Cancer cell plasticity, mainly associated with the epithelial-to-mesenchymal transition in carcinoma, relies on transcriptional, epigenetic or translational reprogramming. In melanoma, an EMT-like dedifferentiation process is characterized by the acquisition of invasive or neural crest stem cell-like features. Herein, we discuss recent findings on the specific roles of phenotypic reprogramming of melanoma cells in driving immune evasion and resistance to immunotherapies. The mechanisms by which dedifferentiated melanoma cells escape T cell lysis, mediate T cell exclusion or remodel the immune microenvironment will be detailed. The expanded knowledge on tumor cell plasticity in melanoma should contribute to the development of novel therapeutic combination strategies to further improve outcomes in this deadly metastatic cancer.

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“…The EMT markers Claudin-1, N-Cadherin, and β-Catenin were significantly inhibited ( Figure 8B ). EMT is reported to drive immune-suppression via the Zeb1 transcription factor, which induces the expression of PDL1 on these invading cells ( 37 ). We thus also checked the level of PDL1 in CSPG4-knockdown cells.…”

Section: Resultsmentioning

confidence: 99%

Co-Expression and Combined Prognostic Value of CSPG4 and PDL1 in TP53-Aberrant Triple-Negative Breast Cancer

Chen

Yang

et al. 2022

Front. Oncol.

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BackgroundIn triple-negative breast cancer (TNBC), PDL1/PD1-directed immunotherapy is effective in less than 20% of patients. In our preliminary study, we have found CSPG4 to be highly expressed together with PDL1 in TNBCs, particularly those harboring TP53 aberrations. However, the clinical implications of co-expressed CSPG4 and PDL1 in TNBCs remain elusive.MethodsA total of 85 advanced TNBC patients treated in the Hunan Cancer Hospital between January 2017 and August 2019 were recruited. The expressions of CSPG4 and PDL1 in TNBC tissues were investigated using immunohistochemistry (IHC). The RNA-seq dataset from the TCGA-BRCA project was further used to analyze the mRNA expression of CSPG4 and PDL1 in TP53-aberrant TNBCs. Cox proportional hazards model and Kaplan–Meier curves with Logrank test was used to analyze the effects of CSPG4 and PDL1 on survival. TNBC cell lines were further used to investigate the molecular mechanism that were involved.ResultsTP53 aberrations occurred in more than 50% of metastatic TNBCs and were related to higher tumor mutation burden (TMB). In TCGA-BRCA RNA-seq dataset analysis, both CSPG4 and PDL1 levels were high in TNBCs, especially in TP53-aberrant TNBCs. IHC assay showed nearly 60% of advanced TNBCs to be CSPG4-positive and about 25% to be both CSPG4-positive and PDL1-positive. The levels of CSPG4 and PDL1 were high in TNBC cell lines as revealed by flow cytometry and immunoblotting compared with non-TNBC cells. Univariate Cox regression analysis indicated that CSPG4 positivity was a significant risk factor for progression-free survival in metastatic TNBCs, with a hazard ratio (HR) of 2.26 (P = 0.05). KM curves with Logrank test also identified high level of CSPG4 as a significant risk factor for overall survival in advanced breast cancers in TCGA-BRCA samples (P = 0.02). The immunoblotting assays showed that EMT-related pathways were involved in CSPG4-mediated invasion.ConclusionsCSPG4 expression level is associated with PDL1 positivity in TP53-aberrant TNBC cells. Patients with CSPG4 expression have poor treatment response and poor overall survival. Co-expressed CSPG4 and PDL1 may have an important prognostic value and provide new therapeutic targets in TNBC patients. CSPG4 might mediate tumor invasion and PDL1 overexpression through EMT-related pathway.

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Zeb1 induces immune checkpoints to form an immunosuppressive envelope around invading cancer cells

Cited by 61 publications

References 62 publications

Immunosuppressive Traits of the Hybrid Epithelial/Mesenchymal Phenotype

Immunosuppressive Traits of the Hybrid Epithelial/Mesenchymal Phenotype

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

Co-Expression and Combined Prognostic Value of CSPG4 and PDL1 in TP53-Aberrant Triple-Negative Breast Cancer

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