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Project

Characterization of bladder cancer immunologic subtypes and immune therapy resistance mechanisms

Funder: Bladder Cancer Advocacy Network

Funding period
USD 2 K
Funding amount
Abstract
Early phase bladder cancer trials of immune checkpoint inhibitors have recently demonstrated very promising results, yet many patients’ tumors still fail to respond. The presence of T cells in the tumor microenvironment has been linked to immunotherapy response and survival in several cancers including urothelial bladder cancer. Tumor-intrinsic molecular mechanisms responsible for T cell exclusion are incompletely defined. The aim of the current proposal will be to identify predisposing factors and acquired molecular mechanisms that lead to T cell exclusion in bladder cancer. We hypothesize that there exists tumor-derived cellular pathways that lead to the absence of T cell infiltration, resulting in resistance to therapy. RNA sequencing and exome somatic mutation data from bladder cancer patients catalogued in the Cancer Genome Atlas (TCGA) will be downloaded. Unsupervised hierarchical clustering will be performed on >15,000 genes. The cluster containing genes from a previously described T cell signature will be used to segregate patients. The groups will then be compared by differential gene expression using ANOVA with a false discovery rate q < 0.01 with a fold change > 2.0. We will also compare somatic variants according to immune phenotype. Enriched pathways will be characterized with Ingenuity Pathways Analysis.Preliminary data suggest beta-catenin activation as correlated with immune exclusion. Other targetable pathways are currently being investigated. Results from this work will aid in the development of novel predictive biomarkers for immunotherapies as well as identify targetable pathways to sensitize non-responding bladder cancer patients to immunotherapy.
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System

Categories
  • FOR (ANZSRC)

    0601 Biochemistry and Cell Biology

  • FOR (ANZSRC)

    1107 Immunology

  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • RCDC

    Biotechnology

  • RCDC

    Human Genome

  • RCDC

    Cancer

  • RCDC

    Genetic Testing

  • RCDC

    Genetics

  • RCDC

    Immunization

  • RCDC

    Urologic Diseases

  • RCDC

    Vaccine Related

  • HRCS HC

    Cancer

  • HRCS RAC

    2.1 Biological and endogenous factors

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science