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Project

Recombinant CCL2 as a novel treatment strategy for bladder cancer

Funder: Bladder Cancer Advocacy Network

Funding period
USD 50 K
Funding amount
Abstract
Recent approval of immunotherapies has revolutionized the approach to managing bladder cancer (BC). Nevertheless, complete response is observed in only a minority of patients and there are no unambiguous biomarkers to guide treatment selection. Currently, a major obstacle in the field is limited knowledge of signals that regulate immune pathways during BC development and growth. The chemokine CCL2 (C-C motif ligand 2) is best known for its ability to induce trafficking of immune cells by binding its primary receptor, CCR2. The recruitment of immunosuppressive cells by CCL2 signaling, promotes cancer in several tumor types. In bladder, however, we show an unexpected finding that CCL2 is protective against BC development and growth. Further, we show that CCL2’s primary receptor, CCR2, is also implicated in bladder cancer defense. We hypothesize that CCL2 mediates protection against bladder tumor growth by recruiting CCR2+ T cells to the bladder environment. To address this hypothesis two specific aims are proposed. In Aim 1, we define mechanisms underlying BC protection by CCR2+ T cells. We utilize the MB49 orthotopic mouse bladder tumor model and antibody depletion studies of T cell subsets and adoptive T cell transfers to define the tumor protective roles of these CCR2+ T cells subsets. Aim 2 investigates contribution of CCL2 towards CCR2-mediated BC protection using antibody depletion of CCL2 (?CCL2) and recombinant CCL2 (rCCL2) in wildtype (WT) versus CCR2KO mice. It also tests a novel nanoparticle formulation of recombinant CCL2 to treat BC. Successful completion of this proposal will elucidate mechanisms underlying CCL2’s protection from BC growth. Data accrued from this proposal are rapidly translatable and could lead to a novel treatment strategies and/or more effective use of existing therapies for patients with BC.
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System

Categories
  • FOR (ANZSRC)

    1107 Immunology

  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • RCDC

    Biotechnology

  • RCDC

    Cancer

  • RCDC

    Urologic Diseases

  • HRCS HC

    Cancer

  • HRCS RAC

    2.1 Biological and endogenous factors

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science