Molecular characterization of neuroendocrine bladder cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 561-561
Author(s):  
Woonyoung Choi ◽  
Jean H. Hoffman-Censits ◽  
Megan Fong ◽  
Noah M. Hahn ◽  
Eva Comperat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Gene Expression Signature ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Molecular Features ◽  
Pathway Gene ◽  
Immune Pathway ◽  
Muscle Invasive ◽  
Whole Transcriptome

561 Background: Neuroendocrine bladder cancer (NEBC) is a rare and aggressive variant that is associated with poor survival outcomes. Because NEBC is rare, the molecular features of NEBC remain poorly characterized. Therefore, we characterized NEBC at the molecular level to understand the underlying biology and identify novel therapeutic targets. Methods: Whole transcriptome RNAseq was performed on FFPE cores from 24 NEBCs and 51 conventional muscle-invasive bladder cancers (MIBCs) from Tenon Hospital in Paris. Results: Unsupervised cluster analysis of 75 tumors generated 2 distinct clusters that separated NEBCs from MIBCs. The NEBC tumors were strongly enriched with biomarkers for the characteristic of neuroendocrine or small cell malignancies, including DLL3, SOX2, and EZH2. In addition, E2F1 pathway is significantly enriched due to the impair of RB/p53 pathways. Further, the NEBCs were enriched with the TCGA’s neuronal differentiation genes that were associated with high response rates in patients treated in atezolizumab (anti-PDL1) within the context of the ImVigor 210 trial. Nevertheless, the NEBCs were characterized by suppressed immune pathway gene expression signatures, such as the Th1 pathway, effector T cell lymphocyte, and IFNg that are usually highly enriched in tumors that are sensitive to immune checkpoint blockade. Of candidate mechanisms, the suppressed TGFbpathway activity observed in the NEBCs was the most obvious explanation for sensitivity to checkpoint blockade. Conclusions: NEBCs are distinct from conventional MIBCs by gene expression signature. They are also characterized by overexpression of canonical neuroendocrine markers and inhibition of TGFb pathway activity.

scholarly journals Sensitization to immune checkpoint blockade through activation of a STAT1/NK axis in the tumor microenvironment

2019 ◽  
Vol 11 (501) ◽  
pp. eaav7816 ◽  
Author(s):  
Rachael M. Zemek ◽  
Emma De Jong ◽  
Wee Loong Chin ◽  
Iona S. Schuster ◽  
Vanessa S. Fear ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Microenvironment ◽  
Nk Cells ◽  
Immune Checkpoint ◽  
Expression Profiles ◽  
Gene Expression Signature ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Poly I:C ◽  
Mouse Strains

Cancer immunotherapy using antibodies that target immune checkpoints has delivered outstanding results. However, responses only occur in a subset of patients, and it is not fully understood what biological processes determine an effective outcome. This lack of understanding hinders the development of rational combination treatments. We set out to define the pretreatment microenvironment associated with an effective outcome by using the fact that inbred mouse strains bearing monoclonal cancer cell line–derived tumors respond in a dichotomous manner to immune checkpoint blockade (ICB). We compared the cellular composition and gene expression profiles of responsive and nonresponsive tumors from mice before ICB and validated the findings in cohorts of patients with cancer treated with ICB antibodies. We found that responsive tumors were characterized by an inflammatory gene expression signature consistent with up-regulation of signal transducer and activator of transcription 1 (STAT1) and Toll-like receptor 3 (TLR3) signaling and down-regulation of interleukin-10 (IL-10) signaling. In addition, responsive tumors had more infiltrating-activated natural killer (NK) cells, which were necessary for response. Pretreatment of mice with large established tumors using the STAT1-activating cytokine interferon-γ (IFNγ), the TLR3 ligand poly(I:C), and an anti–IL-10 antibody sensitized tumors to ICB by attracting IFNγ-producing NK cells into the tumor, resulting in increased cure rates. Our results identify a pretreatment tumor microenvironment that predicts response to ICB, which can be therapeutically attained. These data suggest a biomarker-driven approach to patient management to establish whether a patient would benefit from treatment with sensitizing therapeutics before ICB.

scholarly journals PD-L2 Is Constitutively Expressed in Normal and Malignant Urothelium

2021 ◽  
Vol 11 ◽  
Author(s):  
Alexander C. Dowell ◽  
Haydn Munford ◽  
Anshita Goel ◽  
Naheema S. Gordon ◽  
Nicholas D. James ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Clinical Settings ◽  
Rna Seq ◽  
Muscle Invasive Bladder Cancer ◽  
Urothelial Bladder ◽  
Muscle Invasive ◽  
Normal Urothelium

The use of immune checkpoint blockade, in particular PD-1 and PD-L1 inhibitors, is now commonplace in many clinical settings including the treatment of muscle-invasive bladder cancer (MIBC). Notwithstanding, little information exists regarding the expression of the alternative PD-1 ligand, PD-L2 in urothelial bladder cancer (UBC). We therefore set out to characterise the expression of PD-L2 in comparison to PD-L1. Firstly, we assessed PD-L2 expression by immunohistochemistry and found widespread expression of PD-L2 in UBC, albeit with reduced expression in MIBC. We further investigated these findings using RNA-seq data from a cohort of 575 patients demonstrating that PDCD1LG2 (PD-L2) is widely expressed in UBC and correlated with CD274 (PD-L1). However, in contrast to our immunohistochemistry findings, expression was significantly increased in advanced disease. We have also provided detailed evidence of constitutive PD-L2 expression in normal urothelium and propose a mechanism by which PD-L2 is cleaved from the cell surface in MIBC. These data provide a comprehensive assessment of PD-L2 in UBC, showing PD-L2 is abundant in UBC and, importantly, constitutively present in normal urothelium. These data have implications for future development of immune checkpoint blockade, and also the understanding of the function of the immune system in the normal urinary bladder.

scholarly journals A reported 20-gene expression signature to predict lymph node-positive disease at radical cystectomy for muscle-invasive bladder cancer is clinically not applicable

PLoS ONE ◽  
2017 ◽  
Vol 12 (3) ◽  
pp. e0174039 ◽  
Author(s):  
Kim E. M. van Kessel ◽  
Harmen J. G. van de Werken ◽  
Irene Lurkin ◽  
Angelique C. J. Ziel – van der Made ◽  
Ellen C. Zwarthoff ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Lymph Node ◽  
Radical Cystectomy ◽  
Gene Expression Signature ◽  
Muscle Invasive Bladder Cancer ◽  
Node Positive ◽  
Node Positive Disease ◽  
Lymph Node Positive ◽  
Muscle Invasive

scholarly journals Cytotoxic T-cell-related gene expression signature predicts improved survival in muscle-invasive urothelial bladder cancer patients after radical cystectomy and adjuvant chemotherapy

2020 ◽  
Vol 8 (1) ◽  
pp. e000162 ◽  
Author(s):  
Markus Eckstein ◽  
Pamela Strissel ◽  
Reiner Strick ◽  
Veronika Weyerer ◽  
Ralph Wirtz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Adjuvant Chemotherapy ◽  
Immune Status ◽  
Survival Rates ◽  
Gene Expression Signature ◽  
Cancer Center ◽  
Expression Signature ◽  
Platinum Based Chemotherapy ◽  
Muscle Invasive

BackgroundAssessment of the immune status of muscle-invasive bladder cancer (MIBC) has previously shown to be prognostically relevant after treatment with curative intent. We conducted this study to develop a clinically applicable immune gene expression assay to predict prognosis and adjuvant chemotherapy benefit.Patients and methodsGene expression ofCD3Z,CD8AandCXCL9, immune cell (IC) populations including stromal tumor infiltrating lymphocytes (sTILs), T-cells, natural killer cells (NK-cells), macrophages, Programmed cell death protein 1 positive (PD-1) IC and tumor subtypes (MD Anderson Cancer Center/MDACC-approach) were assessed in 187 MIBC patients (Comprehensive Cancer Center Erlangen-EMN/CCC-EMN-cohort). A gene expression signature was derived by hierarchical-clustering and validated in The Cancer Genome Atlas (TCGA)-cohort. IC populations in the TCGA cohort were assessed via CIBERSORT. Benefit of platinum-containing adjuvant chemotherapy was assessed in a pooled cohort of 125 patients. Outcome measurements were disease specific survival, disease-free survival and overall survival.ResultsThe gene expression signature ofCXCL9,CD3ZandCD8Acorrelates with quantitative amounts of specific IC populations and sTILs (CCC-EMN: ρ-range: 0.44–0.74; TCGA: ρ-range: 0.56–0.82) and allows stratification of three different inflammation levels (inflamed high, inflamed low, uninflamed). Highly inflamed tumors are preferentially basal subtype and show favorable 5-year survival rates of 67.3% (HR=0.27; CCC-EMN) and 55% (HR=0.41; TCGA). Uninflamed tumors are predominantly luminal subtypes and show low 5-year survival rates of 28% (CCC-EMN) and 36% (TCGA). Inflamed tumors exhibit higher levels of PD-1 and Programmed cell death 1 ligand 1 (PD-L1). Patients undergoing adjuvant platinum-based chemotherapy with ‘inflamed high’ tumors showed a favorable 5-year survival rate of 64% (HR=0.27; merged CCC-EMN and TCGA cohort).ConclusionThe gene expression signature ofCD3Z,CD8AandCXCL9can assess the immune status of MIBC and stratify the survival of MIBC patients undergoing surgery and adjuvant platinum-based chemotherapy. Furthermore, the assay can identify patients with immunological hot tumors with particular high expression of PD-L1 potentially suitable for immunotherapy.

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