Tumor-induced immune suppression.

肿瘤引起的免疫抑制。

• 批准号: 7768386
• 负责人: SUZANNE OSTRAND-ROSENBERG
• 金额: $ 25.34万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE COUNTY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-20 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7768386
• 关键词: Active Immunotherapy; Animals; Apoptosis; Breast Adenocarcinoma; Breast Carcinoma; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Patient; Cancer Vaccines; Cells; Data; Development; Dinoprostone; Disease; Disseminated Malignant Neoplasm; Down-Regulation; Excision; Generations; Genes; Goals; Immune; Immunity; Immunocompetent; Immunologic Monitoring; Immunologic Surveillance; Immunosuppression; Immunotherapy; Inflammation; Inflammatory; Interferons; Interleukin-1; Ligands; Link; Malignant Neoplasms; Mediating; Metastatic to; Methods; Mus; Myelogenous; Myeloid Cells; Neoplasm Metastasis; Operative Surgical Procedures; Pathway interactions; Patients; Pharmaceutical Preparations; Primary Neoplasm; Process; Regulation; Resistance; Role; STAT6 Transcription Factor; Signal Transduction; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; Transplantation; Tumor Immunity; cancer cell; cancer immunotherapy; cytokine; gemcitabine; improved; inhibitor/antagonist; macrophage; neoplastic cell; novel; receptor; success; tumor; tumor progression

Novel immunotherapies and cancer vaccines are being developed. The success of these therapies requires an immunocompetent host. Immune suppression occurs in many cancer patients and is a major impediment for developing successful cancer immunotherapies. Although there are numerous types of immune suppression, tumor-induced Myeloid Suppressor Cells (MSC), also known as Immature Myeloid Cells, are found in many patients and in animals with transplanted and spontaneous tumors. We have recently identified in mice a gene, the Signal Transducer and Activator of Transcription 6 (STAT6) gene, that when deleted, results in greatly improved survival and immune rejection of established metastatic mammary carcinoma following surgical removal of primary tumor. Effective tumor-immunity in post-surgery STAT6- deficient mice is mediated by three components: 1) The generation of M1 type macrophages; 2) The generation of tumor-specific CD8+ T cells; and 3) The rapid decrease to baseline in MSC levels. Because MSC accumulation and retention inhibit tumor-specific immunity and interfere with active immunotherapy, we will examine the mechanisms underlying STATG-induced retention of MSC in tumor-bearing mice. We propose the following three Specific Aims to accomplish this goal: 1) Myeloid suppressor cells (MSC) are potent inhibitors of CD4+ and CD8+ T lymphocytes that effectively block tumor-specific immunity. We will identify the ligand/receptor combination responsible for the post-surgery retention of 4T1-induced myeloid suppressor cells. 2) We have previously shown that IFNy is required for the rapid regression of MSC in post- surgery STAT6-deficient mice. We will determine the mechanism responsible for this regression, and will clarify the role of IFN^ in this process. 3) The pro-inflammatory cytokine IL-1/? causes excessive accumulation and retention of MSC in post-surgery mice. We will determine how IL-1¿regulates MSC levels, and ascertain if the link between inflammation and cancer is the induction of MSC. 4) MSC are found in many cancer patients and are thought to be an impediment to immune surveillance and immunotherapy. Using Gemcitabine, a drug that has recently been shown to down-regulate MSC, we will determine if reduction/elimination of MSC by itself is sufficient to mediate tumor rejection and if elimination of MSC impacts M1 macrophages and T lymphocytes. We have hypothesized that MSC block immunosurveillance, thereby facilitating the outgrowth of malignant cells. A better understanding of the regulation of tumor- induced immune suppression may reveal methods for controlling these cells in cancer patients, and thereby contribute to the development of effective cancer immunotherapies.

新的免疫疗法和癌症疫苗正在开发中。这些疗法的成功