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    Research Grants Awarded

    A Novel Target for Preventing Both Immune Tolerance and Tumor Angiogenesis to Improve Immune Enhancing Therapy for Advanced Breast Cancer

    Study Section:
    Tumor Cell Biology III

    Scientific Abstract:
    BACKGROUND: Tumor cells escape attack from the immune system through various mechanisms. We found that the growth of breast carcinomas induces a significant increase in the number of myeloid suppressor cells (MSCs) in tumor infiltrating leukocytes (TILs), spleen, and bone marrow of tumor-bearing mice. MSCs suppress T cell functions through a number of mechanisms, including nitric oxide production, arginine depletion by arginase, and free radicals. We have further shown that sorted Gr-1 + CD115 (M-CSF receptor) + MSCs isolated from spleen and bone marrow of tumor-bearing mice drastically inhibit IFN-g-producing tumor antigen-activated T cells, significantly reduce expression of IL-2 by T cells, induce expression of IL-10, TGF-beta, and the development of T regulatory cells (Treg) that are anergic and suppressive. Furthermore, adoptive transfer of sorted Gr-1 + CD115 + MSC, but not control Gr-1 - CD115 - or Gr-1 + CD115 - cells, can induce tumor specific anergy and Treg development in recipient tumor-bearing mice. These results provide strong evidence of an immunoregulatory function for MSC in vivo in the establishment of tumor-specific tolerance and the development of Treg. More recently, MSCs were found to be able to directly incorporate into tumor vascular endothelium, thereby promoting tumor angiogenesis and metastasis. Therefore, MSC may serve as a novel target for preventing both immune tolerance and tumor angiogenesis. HYPOTHESIS: We hypothesize that controlling MSC accumulation in breast tumor bearing host will not only prevent immune tolerance and Treg development but also inhibit tumor angiogenesis and metastasis. SPECIFIC AIMS: Three aims will be pursued in order to control the tumor growth and metastases and to achieve long term cure for breast cancer: 1) To study the mechanisms underlying the accumulation and differentiation of MSC in breast tumor-bearing mice; 2) To study the effect of neutralization of tumor factors on MSC-mediated tumor specific T regulatory cells induction, T cell inactivation, and angiogenesis; and 3) To determine whether the prevention of MSC accumulation, thereby preventing MSC-mediated immune suppression, Treg development, and tumor angiogenesis, can improve the efficacy of immune modulatory therapy in an advanced breast cancer setting. STUDY DESIGN: Neutralizing antibodies, soluble cytokine receptors, and siRNA (RNA silencing) will be used to study the role of tumor factors in the accumulation of MSC and the development of Treg and T-cell tolerance. Synergistic effect of blockade of MSC development and functions with our immune activation protocol (IL-12 gene delivery and 4-1BB activation) will be accessed in mice bearing advanced mammary tumors. POTENTIAL OUTCOMES AND BENEFITS: Successful completion of these studies will result in a better understanding of the role of MSC mediate immune suppression and metastases in breast tumor bearing host and more importantly serve as the scientific foundation for devising a novel treatment modality to specifically target MSC to prevent immune suppression, angiogenesis, and metastasis. The ablation of MSC accumulation and the inhibition of MSC functions should significantly augment the efficacy of our immune activation protocol (ADV/IL-12 gene + 4-1BB activation by 4-1BB ligand-Ig fusion protein) for patients with advanced breast cancer.

    Lay Abstract:
    BACKGROUND: Despite significant progress in chemotherapy for breast cancer achieved over the past three decades, approximately 25% of Stage I and II patients will have a systemic recurrence within ten years of diagnosis. The figure approaches 50% for patients with stage III disease. For residual and metastatic disease, conventional chemotherapeutic regimens and hormonal therapies are considered palliative, with a response rate of 10% and median survival time of 18-24 months. Therefore, deriving an effective treatment modality to prevent and/or eradicate metastatic diseases become paramount to future developments for breast cancer therapy. Currently the best avenues to control tumor metastases are prevention of the angiogenesis at the tumor site and immune activation to eradicate the micro-metastatic tumors. We have used the immune activation therapy for the eradication of metastatic tumors; however, the therapeutic effect was significantly suppressed by the immune suppressor cells, e.g. myeloid suppressor cells and T regulatory cells (Treg), in hosts with advanced malignancy. We found that the growth of breast carcinomas induced a significant increase in the number of myeloid suppressor cells (MSC) in tumor infiltrating leukocytes (TILs), spleen, and bone marrow of tumor-bearing mice. We have further shown that purified MSC isolated from spleen and bone marrow of tumor-bearing mice drastically inhibit IFN-g-producing tumor antigen-activated T cells, induce the expression of NO, IL-10, TGF-beta, and induce the development of regulatory T cells that suppress the activated T cell immune response. More recently, MSCs were found to promote tumor angiogenesis (blood vessel formation) and metastases. Therefore, MSC is an ideal target for blocking immune suppression, tumor angiogenesis, and metastasis. OBJECTIVE/HYPOTHESIS: Our goal is to identify tumor factors that regulate the accumulation of MSC and to develop a novel therapeutic modality to counteract both T-cell tolerance and tumor angiogenesis by targeting MSC. We hypothesize that immune enhancing therapy for the treatment of advanced and metastatic breast cancers can be significantly improved by blocking the accumulation and suppressive activities of MSC. SPECIFIC AIMS: We will: 1) identify factors that regulate the accumulation and differentiation of MSC in breast tumor-bearing mice; 2) study the effect of neutralization of tumor factors on MSC-mediated tumor specific T regulatory cells induction, T cell inactivation, and angiogenesis; and 3) determine whether the prevention of MSC accumulation, thereby preventing MSC-mediated immune suppression, Treg development, and tumor angiogenesis, can improve the efficacy of immune modulatory therapy in an advanced breast cancer setting. STUDY DESIGN: Neutralizing antibodies and siRNA (RNA silencing) will be used to study the role of tumor factors in the accumulation of MSC and the development of Treg and T-cell tolerance. Synergistic effect of blockade of MSC development and functions with our immune activation protocol (IL-12 gene delivery and 4-1BB activation) will be accessed in mice bearing advanced mammary tumors. POTENTIAL OUTCOMES AND BENEFITS: Our novel strategy to target MSC for the prevention of both immune tolerance and tumor angiogenesis will greatly improve the efficacy of our current immune activation clinical protocol (IL-12 gene delivery + 4-1BB activation) for the treatment of advanced and metastatic breast cancer.