EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer

Wang, Li; Saci, Abdel; Szabó, Péter M.; Chasalow, Scott D.; Castillo-Martín, Mireia; Domingo-Domènech, Josep; Siefker-Radtke, Arlene; Sharma, Padmanee; Sfakianos, John P.; Gong, Yixuan; Dominguez-Andres, Ana; Oh, William; Mulholland, David J.; Azrilevich, Alex; Hu, Liangyuan; Cordon‐Cardo, Carlos; Salmon, Hélène; Bhardwaj, Nina; Zhu, Jun; Galsky, Matthew D.

doi:10.1038/s41467-018-05992-x

Cited by 235 publications

(225 citation statements)

References 50 publications

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“…More recently, Moriggi et al reported that fibrinogen, encoded by FGB, is involved in ECM remodeling, including the epithelial-mesenchymal transition (EMT) [44]. Matthew D. Galsky further confirmed that EMT-related gene expression and T-cell infiltration are positively correlated, and the balance of T-cell vs. EMT/stromal elements may have prognostic/predictive implications with the antitumor immune response [45].…”

Section: Discussionmentioning

confidence: 95%

Identification and validation of stromal-tumor microenvironment-based subtypes tightly associated with PD-1/PD-L1 immunotherapy and outcomes in patients with gastric cancer

et al. 2020

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Background: Immunotherapies targeting programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) have been approved for gastric cancer (GC) patients. However, a large proportion of patients with T-cell-inflamed tumor microenvironment do not respond to the PD-1/PD-L1 blockade. The stromal component of the tumor microenvironment has been associated with immunotherapy. This study aims to explore the clinical significance of the nonimmune cells in the tumor microenvironment and their potential as biomarkers for immunotherapy. Methods: A total of 383 patients with GC from the Cancer Genome Atlas (TCGA) cohort, 300 patients with GC from the GSE62254 cohort in Gene Expression Omnibus (GEO) were included in the study. A stromal score was generated using the ESTIMATE algorithm, and the likelihood of response to PD-1/PD-L1 immunotherapy of GC patients was predicted using the TIDE algorithm. The prognostic value of the stromal score from GC cases was evaluated by the Kaplan-Meier method and Cox regression analysis. Gene set enrichment analysis (GSEA) was also conducted. Results: The stromal score showed significant differences in different molecular subtypes and T stages. Multivariate analyses further confirmed that the stromal score was an independent indicator of overall survival (OS) in the two cohorts. The low stromal score group showed higher tumor mutation burden (TMB) and micro-satellite instability (MSI), and was more sensitive to immune checkpoint inhibitor according to the TIDE algorithm. Activation of the transforming growth factor and epithelial-mesenchymal transition were observed in the high stromal score subtype, which is associated with T-cell suppression, and may be responsible for resistance to PD-1/PD-L1 therapy. BPIFB2 was confirmed as a hub gene relevant to immunotherapy. Conclusion: The stromal score was associated with cancer progression and molecular subtypes, and may serve as a novel biomarker for predicting the prognosis and response to immunotherapy in patients with GC.

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Section: Discussionmentioning

confidence: 95%

Identification and validation of stromal-tumor microenvironment-based subtypes tightly associated with PD-1/PD-L1 immunotherapy and outcomes in patients with gastric cancer

et al. 2020

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“…Tumor metastasis begins with epithelial-mesenchymal transition (EMT), in which epithelial cells acquire a mesenchymal phenotype and become migratory and invasive (Shen et al, 2017;Wang et al, 2018). Loss of the epithelial marker E-cadherin and an increase in the expression of mesenchymal markers are characteristics of EMT.…”

Section: Introductionmentioning

confidence: 99%

EMT-related gene expression is positively correlated with immunity and may be derived from stromal cells in osteosarcoma

Peng

Qin

et al. 2020

PeerJ

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Background Osteosarcoma is the most common type of bone cancer in children and young adults. Recent studies have shown a correlation between epithelial–mesenchymal transition (EMT)-related gene expression and immunity in human cancers. Here, we investigated the relationship among EMT, immune activity, stromal activity and tumor purity in osteosarcoma. Methods We defined EMT gene signatures and evaluated immune activity and stromal activity based on the gene expression and clinical data from three independent microarray datasets. These factors were evaluated by single sample Gene Set Enrichment Analyses and the ESTIMATE tool. Finally, we analyzed the key source of EMT gene expression in osteosarcoma using microarray datasets from the Gene Expression Omnibus and human samples that we collected. Results EMT-related gene expression was positively correlated with immune and stromal activity in osteosarcoma. Tumor purity was negatively correlated with EMT, immune activity and stromal cells. We further demonstrated that high EMT gene expression could significantly predict poor overall survival (OS) and recurrence-free survival (RFS) in osteosarcoma patients, while high immune activity cannot. However, combining these factors could have further prognostic value for osteosarcoma patients in terms of OS and RFS. Finally, we found that stromal cells may serve as a key source of EMT gene expression in osteosarcoma. Conclusion The results of this study reveal that the expression of EMT genes and immunity are positively correlated, but these signatures convey disparate prognostic information. Furthermore, the results indicate that EMT-related gene expression may be derived from stromal rather than epithelial cancer cells.

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“…Indeed, a subset of BATF3 + IRF8 + cDC1s are not only required for T cell trafficking, but are also necessary for the generation of effector T cell responses to anti-PD-1 therapy (17,135). Importantly, processes of metastasis co-opted by tumors such as EMT also influence DC maturation, migration, and phenotype, and are associated with ICB resistance in both melanoma and bladder cancer (136,137). These studies highlight the importance of DCs in ICB and suggest that targeting DCs to reverse tolerogenesis may sensitize previously unresponsive patients to ICB.…”

Section: Tolerization and Checkpoint Inhibitor Immunotherapymentioning

confidence: 99%

Role of Tumor-Mediated Dendritic Cell Tolerization in Immune Evasion

et al. 2019

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The vast majority of cancer-related deaths are due to metastasis, a process that requires evasion of the host immune system. In addition, a significant percentage of cancer patients do not benefit from our current immunotherapy arsenal due to either primary or secondary immunotherapy resistance. Importantly, select subsets of dendritic cells (DCs) have been shown to be indispensable for generating responses to checkpoint inhibitor immunotherapy. These observations are consistent with the critical role of DCs in antigen cross-presentation and the generation of effective anti-tumor immunity. Therefore, the evolution of efficient tumor-extrinsic mechanisms to modulate DCs is expected to be a potent strategy to escape immunosurveillance and various immunotherapy strategies. Despite this critical role, little is known regarding the methods by which cancers subvert DC function. Herein, we focus on those select mechanisms utilized by developing cancers to co-opt and tolerize local DC populations. We discuss the reported mechanisms utilized by cancers to induce DC tolerization in the tumor microenvironment, describing various parallels between the evolution of these mechanisms and the process of mesenchymal transformation involved in tumorigenesis and metastasis, and we highlight strategies to reverse these mechanisms in order to enhance the efficacy of the currently available checkpoint inhibitor immunotherapies.

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EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer

Cited by 235 publications

References 50 publications

Identification and validation of stromal-tumor microenvironment-based subtypes tightly associated with PD-1/PD-L1 immunotherapy and outcomes in patients with gastric cancer

Identification and validation of stromal-tumor microenvironment-based subtypes tightly associated with PD-1/PD-L1 immunotherapy and outcomes in patients with gastric cancer

EMT-related gene expression is positively correlated with immunity and may be derived from stromal cells in osteosarcoma

Role of Tumor-Mediated Dendritic Cell Tolerization in Immune Evasion

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