Please enable JavaScript or talk to your local administrator to get JavaScript enabled.

Project

Effect of APOBEC3 on Bladder Cancer Biology and Response to Immunotherapy

Funder: National Cancer Institute

Funding period
USD 45 K
Funding amount
Abstract
PROJECT SUMMARY The apolipoprotein B mRNA editing enzyme catalytic polypeptide 3 (APOBEC3) family of proteins play an important role in innate immunity by restricting retroviral replication. During a viral infection, these enzymes are upregulated by interferon signaling. They catalyze the conversion of cytidine to uracil within reverse-transcribed, single-stranded DNA, resulting in the degradation or integration of defective viral nucleic acid, and therefore, impaired viral replication. During DNA replication and transcription in mammalian cells, single-stranded DNA can also serve as the substrate for APOBEC3 enzymes. Given the highly proliferative nature of cancer cells, and a high level of interferon signaling in certain cancer types, APOBEC-induced mutagenesis can contribute significantly to their mutational spectrum. In cancer, high APOBEC expression correlates with an increased tumor mutational burden (TMB) and predicted neoantigen load. Studies in vitro and in liver cancer transgenic mouse models have shown that APOBEC overexpression can promote tumor progression. In urothelial carcinoma, the expression of APOBEC3B, a particular member of this protein family, is significantly upregulated. Strikingly, upwards of 70% of mutations can be attributed to APOBEC-induced mutagenesis. I have generated mouse bladder cancer cell lines with inducible murine Apobec3. I confirmed the induction of Apobec3 protein, induction of an APOBEC mutational pattern, and the ability of Apobec3 to promote anchorage-independent growth. In addition, we have generated a novel Rosa26-Apobec3 knock-in allele in which the expression of Apobec3 is Cre-inducible, allowing for spatial and temporal control of Apobec3 expression. Currently, no studies have examined APOBEC's role in mediating intratumoral heterogeneity, or in response to immune checkpoint blockade. High intratumoral heterogeneity has been shown to negatively correlate with response to immunotherapy. Additionally, because of the increased mutational load (and therefore, neoantigens) imparted by APOBEC-induced mutagenesis, one would expect a robust response to immune checkpoint blockade. However, many of the neoantigens may be subclonal and persistent APOBEC mutagenesis, in the context of a neoantigen driven anti-tumor immune response, may allow for antigen escape (i.e. due to nonsense mutations in the gene encoding the neoantigen). I will utilize the tools we have developed to answer these important questions. Specifically, in Aim 1, I will cross our novel Apobec3 knock-in allele to our established Pten and Trp53-deficient mouse model of bladder cancer and characterize the intratumoral heterogeneity by multiregional whole-exome sequencing. In Aim 2, I will utilize an allograft bladder cancer model with inducible Apobec3 to test whether Apobec3 mutagenic activity can dampen the efficacy of immunotherapy. Results of the proposed aims will contribute to a greater understanding of the role of APOBEC3 mutagenesis in fueling the evolution of bladder cancer. This expansion of knowledge will provide the rationale to develop more effective treatments for bladder cancer such as an APOBEC3 inhibitor.
Similar projects All >
Sorted by: Start Date
Project list item
Targeting regulatory B cells (Bregs) to improve anti-bladder cancer immunity

Bladder Cancer Advocacy Network to Burles Avner Johnson, David McConkey

USD 50,000
2020 - 2021
Project list item
Dissecting myeloid cell-mediated resistance to immune checkpoint blockade in bladder cancer

National Cancer Institute to NINA BHARDWAJ, JUN ZHU, MATTHEW GALSKY

USD 703,400
2020 - 2025
Project list item
Unravelling Mechanisms of Resistance to Checkpoint Inhibition in Canine Urothelial Carcinoma

V Foundation for Cancer Research to Nicola J. Mason

USD 500,000
2019 - 2021
Project list item
Phase 1/2 Study of Modern Immunotherapy in BCG-Relapsing Urothelial Carcinoma of the Bladder - (ADAPT-BLADDER)

National Cancer Institute to NOAH M HAHN

USD 1,313,632
2019 - 2024

System

Categories
  • FOR (ANZSRC)

    0601 Biochemistry and Cell Biology

  • FOR (ANZSRC)

    1107 Immunology

  • RCDC

    Biotechnology

  • RCDC

    Cancer

  • RCDC

    Genetics

  • RCDC

    Immunization

  • RCDC

    Urologic Diseases

  • HRCS HC

    Cancer

  • HRCS RAC

    2.1 Biological and endogenous factors

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science