Dataset Information

Unwrapping the genomic characteristics of urothelial bladder cancer and successes with immune checkpoint blockade therapy.

ABSTRACT: Urothelial bladder cancer (UBC) is one of the most common lethal cancer worldwide and the 5-year survival rate has not improved significantly with current treatment protocols during the last decade. Intravesical immunotherapy with Bacillus Calmette-Guérin is currently the standard care for non-muscle invasive UBC. Recently, a subset of patients with locally advanced or metastatic UBC have responded to checkpoint blockade immunotherapy against the programmed cell death 1 protein (PD-1) or its ligand (PD-L1) or the cytotoxic T-lymphocyte antigen 4 that releases the inhibition of T cells, the remarkable clinical efficacy on UBC has brought total five checkpoint inhibitors approved by the FDA in the last 2 years, and this is revolutionizing treatment of advanced UBC. We discuss the rationale for immunotherapy in bladder cancer, progress with blocking the PD-1/PD-L1 pathway for UBC treatment, and ongoing clinical trials. We highlight the complexity of the interactions between cancer cells and the immune system, the genomic basis for response to checkpoint blockade immunotherapy, and potential biomarkers for predicting immunotherapeutic response.

SUBMITTER: Cheng W

PROVIDER: S-EPMC5833720 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Unwrapping the genomic characteristics of urothelial bladder cancer and successes with immune checkpoint blockade therapy.

Cheng Wen W Fu Dian D Xu Feng F Zhang Zhengyu Z

Oncogenesis 20180123 1

Urothelial bladder cancer (UBC) is one of the most common lethal cancer worldwide and the 5-year survival rate has not improved significantly with current treatment protocols during the last decade. Intravesical immunotherapy with Bacillus Calmette-Guérin is currently the standard care for non-muscle invasive UBC. Recently, a subset of patients with locally advanced or metastatic UBC have responded to checkpoint blockade immunotherapy against the programmed cell death 1 protein (PD-1) or its lig ...[more]

PMID: 29358573

Similar Datasets

Project description:BackgroundBladder urothelial carcinoma (BLCA) is one of the most common urinary tract malignant tumors. Immune checkpoint blockade (ICB) therapy has significantly progressed the treatment of BLCA. This study aimed to investigate the role of specific genetic mutations that may serve as immune biomarkers for ICB therapy in BLCA.MethodsMutation information and expression profiles were acquired from The Cancer Genome Atlas (TCGA) database. Integrated bioinformatics analysis was carried out to explore the subtypes with poor prognosis of BLCA. Functional enrichment analysis was also conducted. The infiltrating immune cells and the prediction of ICB response between different subtypes were explored using the immuCellAI algorithm. Cell Counting Kit-8 (CCK-8) and flow cytometry assays were conducted to explore the effect of filaggrin (FLG) knockdown in BLCA 5637 and T24 cell lines.ResultsAn overview of mutation information in BLCA patients was shown. FLG was identified to be strongly associated with the prognosis of BLCA patients and FLG wild-type was associated with poorer outcome. Prognostic FLG wild-type was divided into 2 subtypes (Sub1 and Sub2). Following an investigation of the subtypes, Sub2 of FLG wild-type was found to be associated with poorer outcome in BLCA. The differentially expressed genes (DEGs) between Sub1 and Sub2 were screened out and the DEGs were enriched in malignant tumor proliferation, DNA damage repair, and immune-related pathways. Furthermore, Sub2 of FLG wild-type was associated with infiltrated immune cells, and responded worse to ICB. Sub2 of FLG wild-type may be used as a biomarker to predict the prognosis of BLCA patients receiving ICB. The cellular experiments revealed that knockdown of FLG could suppress BLCA cell proliferation and promote apoptosis.ConclusionsFLG is an oncogene that may affect the prognosis of BLCA patients through mutation. Sub2 of FLG wild-type is associated with poor prognosis and can be used to predict ICB response for BLCA treatment. This research provides a new basis and ideas for guiding the clinical application of BLCA immunotherapy.

Project description:Immune checkpoint inhibitors (ICI) are used in the treatment of urothelial and renal cell cancers. While some patients may have exceptional responses, better predictive biomarkers are needed. We profiled the circulating immune compartment of patients receiving ICI to identify possible immune markers associated with immunotherapy response or resistance. Peripheral blood samples were collected prior to, and 3 weeks after initiation of ICI. Using mass cytometry, 26 distinct immune populations were identified. Responders to immune checkpoint inhibitors had higher frequencies of naïve CD4+ T-cells, and lower frequencies of CD161+ Th17 cells and CCR4+ Th2 cells. Non-responders had a higher frequency of circulating PD1+ T-cells at baseline; there was a subsequent decrease in frequency with exposure to ICI with a concomitant increase in Ki67 expression. Flow cytometry for cytokines and chemokine receptors showed that CD4+ T cells of non-responder patients expressed less CXCR4 and CCR7. In addition, their PD1- CD4+ T cells had higher TNFα and higher CCR4 expression, while their PD1+ CD4+ T cells had higher interferon γ and lower CCR4 expression. The role of γ/δ T-cells was also explored. In responders, these cells had higher levels of interferon γ, TNFα and CCR5. One patient with a complete response had markedly higher frequency of γ/δ T-cells at baseline, and an expansion of these cells after treatment. This case was analyzed using single-cell gene expression profiling. The bulk of the γ/δ T cells consisted of a single clone of Vγ9/Vδ2 cells both before and after expansion, although the expansion was polyclonal. Gene expression analysis showed that exposure to an ICI led to a more activated phenotype of the γ/δ T cells. In this study, the circulating immune compartment was shown to have potential for biomarker discovery. Its dynamic changes during treatment may be used to assess response before radiographic changes are apparent, and these changes may help us delineate mechanisms that underpin both response and resistance to ICI. It also hypothesizes a potential role for γ/δ T cells as effector cells in some cases.

Dataset Information

Unwrapping the genomic characteristics of urothelial bladder cancer and successes with immune checkpoint blockade therapy.

Publications

Unwrapping the genomic characteristics of urothelial bladder cancer and successes with immune checkpoint blockade therapy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets