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    Research Grants Awarded

    Uric Acid Crystals as a Novel Adjuvant for HER-2/neu-Based Immunotherapy in a Somatic Mammary Carcinoma Model

    Study Section:
    Tumor Cell Biology III

    Scientific Abstract:
    Background: HER-2/neu, a member of the epidermal growth factor receptor family that is overexperessed in many breast and ovarian cancers, is an immunogen for cancer vaccination. However, a major hurdle in breast cancer immunotherapy for humans is the shortage of an effective adjuvant. The crystal of monosodium urate (MSU), which is overproduced by necrotic or apoptotic cells due to accelerated degradation of DNA and RNA, can function as a “danger” signal of injured cells to alert the immune system by promoting dendritic cells (DC) maturation and antigen presentation. Our study showed that MSU can activate a P2X7-like receptor and induce MICA/B (MHC class I-related chain A/B, the ligands for NKG2D activation receptor in T and NK cells) expression in DC and tumor cells. Objectives/Hypothesis: We hypothesize that MSU can be used as a novel adjuvant in HER-2/neu-based immunotherapy. The objectives of our study are to examine its adjuvant effect for HER-2/neu-based immunotherapy in controlling breast cancer in a novel murine somatic breast cancer model and to understand the molecular and immunological mechanisms of action of MSU. Specific aims: 1) To test whether HER-2/neu vaccination with MSU can prevent and control HER-2/neu-induced mammary carcinomas; 2) To study the immunological mechanism of MSU-assisted immunotherapy; 3) To identify the molecular target of MSU. Study design: Mammary carcinomas will be induced in TVA (TVA, tumor virus A, a receptor for avian retrovirus) transgenic mice (under the control of the MMTV promoter) by intraductal injection of a retroviral vector encoding the mouse HER-2/neu gene. We propose to: 1) test whether MSU as an adjuvant in HER-2/neu-based immunotherapy can control breast cancer in these mice; 2) test whether MSU can stimulate the production of anti-HER-2/neu antibody, activate CD4 and CD8 T cells and determine which type of immune cells is required to prevent and/or control HER-2/neu breast cancer; 3) identify the target of MSU by using the expression cloning approach. Potential outcomes and benefits of the research: O ur study will demonstrate the efficacy and efficiency of MSU as an adjuvant for immunotherapy to control breast cancer in a clinically relevant mouse model. MSU has great potential as a novel adjuvant for HER-2/neu-based immunotherapy in humans. Identification of the receptor for MSU may allow the development of new adjuvant.

    Lay Abstract:
    HER-2/neu, an oncogenic molecule that is overexpressed in 10-30% of breast and ovarian cancers, can be used as a vaccine to control breast cancer in animal models. Clinical studies have shown that HER-2/neu vaccination can increase the number of tumor-specific immune cells in the patient’s blood. However, the therapeutic effect seen in animal models has not been translated in a clinical setting. HER-2/neu-based immunotherapy in clinical trials has only induce a partial immune response, which is misplaced and too little and weak to kill tumor cells. The disparity in the outcome of this immunotherapy between mice and humans is because: 1) the mammary carcinomas induced in mouse models are incompatible with human cancer; 2) Powerful adjuvants used in experimental animal models cannot be used in humans due to severe side effects. In this grant application, we propose to study the therapeutic effect of a novel adjuvant in a clinically relevant mouse model in which breast cancer will be induced at any age by overexpression of the HER-2/neu gene in a few ductal epithelial cells. We will use this unique model to test whether the crystals of uric acid, which have been shown to activate immune cells of both mice and humans in vitro and to have a pronounced adjuvant effect in vivo, can be developed as a novel adjuvant for HER-2/neu-based immunotherapy to control and/or prevent breast cancer. We will next determine what immune responses are induced by uric acid crystals, and which response is required to prevent and/or control breast cancer onset and growth. Finally, we propose to identify the molecular target of uric acid crystal. We anticipate that our proposed studies will tell us how effectively uric acid can potentiate HER-2/neu-based immunotherapy. Demonstration that uric acid is superior to the existing adjuvants will allow the development of a new regimen in immunotherapy. Uric acid in combination with current agents such as GM-CSF may achieve a synergistic adjuvant effect. Our studies will also gain many novel insights into the mechanisms of action of uric acid crystal. Identification of the receptor of uric acid crystal will allow the development of additional new adjuvants.