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Project

Targeting regulatory B cells (Bregs) to improve anti-bladder cancer immunity

Funder: Bladder Cancer Advocacy Network

Funding period
USD 50 K
Funding amount
Abstract
Immunotherapy has transformed treatment for patients with urothelial carcinoma of the bladder (UCB) by blocking immune ‘checkpoint pathways’ that impede successful anti-tumor immunity. Unfortunately, most patients with metastatic UCB do not have a clinical response to immunotherapy, and will die of their disease. Resistance to immunotherapy is likely driven by immune suppression that prevents anti-tumor immunity. Therefore, an understanding of mechanisms driving immunosuppression is needed to develop new therapies for metastatic UCB. Recently, B cells have been implicated in the response to immunotherapy in several cancers. In advanced melanoma, high expression of an intratumoral pan-B cell gene signature associates with response to immunotherapy, but expression of a signature consistent with immune suppressive B cells (Bregs) correlates with lack of response. Limited data also indicates that both stimulatory B cells and Bregs can modulate UCB pathogenesis. My preliminary data shows that in a model of UCB, tumors grow more slowly in mice lacking B cells, suggesting a subset of Bregs may suppress immunity in UCB. Therefore, my central hypothesis is that while stimulatory B cells can provoke an anti-tumor response in UCB, Bregs can inhibit immunity. These Bregs can be targeted to improve survival. To test my central hypothesis, I propose these Specific Aims: Aim 1: Define how eliminating Bregs impact tumor growth in murine UCB models.Aim 2: Define B cell-associated transcriptional signatures associated with clinically-aggressive biology and resistance to immunotherapy. To complete the proposed work, we will use genetic and pharmacologic techniques to eliminate B cells and Bregs in mouse models, and therapy responsive and resistant tumors from patients with UCB. We expect that the proposed research will have strong impact in UCB by identifying novel methods to target Bregs that can be quickly transitioned to clinical trials.
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System

Categories
  • FOR (ANZSRC)

    1107 Immunology

  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • RCDC

    Cancer

  • RCDC

    Genetics

  • RCDC

    Immunization

  • RCDC

    Vaccine Related

  • HRCS HC

    Cancer

  • HRCS RAC

    2.1 Biological and endogenous factors

  • HRCS RAC

    5.1 Pharmaceuticals

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Clinical Medicine and Science