G-CSF inhibition as a colorectal cancer therapy

G-CSF 抑制作为结直肠癌治疗

• 批准号: 9789196
• 负责人: Ellen J. Beswick
• 金额: --
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-06 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789196
• 关键词: Antibody Therapy; Bone Marrow; CD8-Positive T-Lymphocytes; Cancer Etiology; Cancer Model; Cell Proliferation; Cells; Cessation of life; Chemotherapy-Oncologic Procedure; Colitis; Colony-Stimulating Factor Overexpression; Colony-Stimulating Factor Receptors; Colorectal Cancer; Colorectal Neoplasms; Data; Development; Diagnosis; Disease; Disease Outcome; Granulocyte Colony-Stimulating Factor; Human; Immune; Immune response; Immune system; Individual; Inflammatory; Interleukin-10; Knowledge; Laboratories; Lead; Lytic; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Metastatic Neoplasm to Lymph Nodes; Metastatic Neoplasm to the Liver; Mus; Myeloid Cells; Natural Killer Cells; Neoplasm Metastasis; Pathology; Pathway interactions; Patients; Population; Process; Production; Regulatory T-Lymphocyte; Role; Sampling; T cell response; T-Lymphocyte; Testing; Therapeutic; Tissue Sample; Tissues; Tumor Escape; Tumor Immunity; Tumor Tissue; United States; cancer stem cell; clinical care; colitis associated cancer; colorectal cancer metastasis; colorectal cancer progression; colorectal cancer treatment; cytokine; cytotoxic; fighting; human tissue; improved; knock-down; macrophage; metastatic colorectal; migration; mortality risk; mouse model; neoplasm regression; neoplastic cell; neutrophil; new therapeutic target; novel; novel therapeutics; overexpression; prevent; response; stem-like cell; success; translational approach; tumor; tumor growth; tumor immunology; tumor microenvironment; tumor progression

Project Summary: Colorectal cancer conveys a high mortality risk as the second most common cause of cancer in the US. While newer chemotherapy regimens have improved survival, 37% of all patients diagnosed with CRC in the United States will die of this disease. Clearly, new tumor targets are needed to develop improved treatment approaches. Harnessing natural anti-tumor immunity is a promising approach to develop new therapies. develop new therapies. We have found that one potential way to do this is by blocking a critical cytokine that induces tumor cell proliferation and invasion along with inhibitory immune responses in CRC. Granulocyte colony-stimulating factor (G-CSF) is a key cytokine present in 88% of human colorectal tumors. Blockade of this cytokine in a mouse model of colorectal cancer led to activation of protective immune responses and neoplasm regression. G-CSF may induce regulatory T cell accumulation and potent inhibition of cytotoxic cell responses. Since these responses may have critical tumor promoting functions, we hypothesize that G-CSF blockade is protective in CRC by inhibiting tumor progression and inducing anti-tumor immunity. To test this hypothesis, the following Specific Aims will be completed: Specific Aim 1: Delineate the role of G-CSF/G-CSFR in colorectal cancer progression and the potential of blockade as a therapeutic approach. We hypothesize that G-CSF/G-CSFR inhibition will prevent or regress colorectal cancer metastasis. This will be examined by knocking down G-CSF/G-CSFR in tumor cells, overexpressing G-CSF/G-CSFR in tumor cells, and employing therapeutic approaches in mouse models of CRC metastasis. Human CRC tissues will be examined for an association with G-CSF/G-CSFR expression and metastasis. Specific Aim 2: Delineate the role of G-CSF/G-CSFR inhibition on enhancing anti-tumor immunity to protect against CRC progression. We hypothesize that G-CSF induces a tumor immune evasive microenvironment by inducing immune cell IL-10 production and by inhibiting cytotoxic immune cell responses. The direct effects of G-CSF on myeloid cell and T cell IL-10 production will be examined. The direct effects of G-CSF on NK and CD8+ T cells will be examined along with indirect effects through modulation of IL-10 in the tumor microenvironment will be examined. The ability of G-CSF to inhibit NK cell and CD8+ T cell tumor lytic function will be assessed. Human CRC and liver metastasis tissues with high vs low G-CSF/G-CSFR expression will be examined for NK and CD8+ T cell activity. Thus, for this project, we will examine multiple mechanisms of G-CSF blockade on tumor proliferation and invasion, activation of protective myeloid and T cell responses, and test blockade of this pathway in an invasive colorectal cancer model and in human tumor tissues in translational approaches that could lead to a new treatment for colorectal cancer.

项目概要： 结直肠癌作为美国第二大常见癌症原因，具有高死亡率风险。而 新的化疗方案提高了生存率，在美国，37%的CRC患者被诊断为 国家将死于这种疾病。显然，需要新的肿瘤靶点来开发改进的治疗方法 接近。利用天然抗肿瘤免疫是开发新疗法的一种有前途的方法。 开发新的疗法。我们已经发现，一种潜在的方法是通过阻断一种关键的细胞因子， 在CRC中诱导肿瘤细胞增殖和侵袭沿着抑制性免疫应答。粒细胞 集落刺激因子（G-CSF）是存在于88%的人类结肠直肠肿瘤中的关键细胞因子。封锁 这种细胞因子在结肠直肠癌小鼠模型中导致保护性免疫应答的激活， 肿瘤消退。G-CSF可诱导调节性T细胞聚集，并有效抑制细胞毒性细胞增殖。 应答由于这些反应可能具有重要的肿瘤促进功能，我们假设G-CSF可能与肿瘤的发生有关。 阻断通过抑制肿瘤进展和诱导抗肿瘤免疫在CRC中具有保护性。到 为了检验这一假设，将完成以下具体目标： 具体目标1：阐明G-CSF/G-CSFR在结直肠癌进展中的作用以及其潜在的 作为一种治疗方法。我们假设G-CSF/G-CSFR抑制将阻止或 消退结肠直肠癌转移。这将通过敲低肿瘤细胞中的G-CSF/G-CSFR来检查， 在肿瘤细胞中过表达G-CSF/G-CSFR，并在小鼠肿瘤模型中采用治疗方法， CRC转移。将检查人CRC组织与G-CSF/G-CSFR表达的相关性 和转移。 具体目标2：描述G-CSF/G-CSFR抑制对增强抗肿瘤免疫的作用， 防止CRC进展。我们假设G-CSF诱导肿瘤免疫逃避， 通过诱导免疫细胞IL-10产生和抑制细胞毒性免疫细胞应答来调节微环境。 将检查G-CSF对骨髓细胞和T细胞IL-10产生的直接影响。的直接影响 将沿着检查G-CSF对NK和CD 8 + T细胞的作用以及通过调节IL-10对NK细胞和CD 8 + T细胞的间接作用。 将检查肿瘤微环境。G-CSF抑制NK细胞和CD 8 + T细胞肿瘤溶解的能力 功能将被评估。具有高vs低G-CSF/G-CSFR的人CRC和肝转移组织 将检查NK和CD 8 + T细胞活性的表达。 因此，在这个项目中，我们将研究G-CSF阻断肿瘤增殖的多种机制， 侵袭、保护性髓样和T细胞应答的激活，以及在侵袭性细胞中测试该途径的阻断。 结肠直肠癌模型和人类肿瘤组织中的翻译方法，可能导致一种新的 结肠直肠癌的治疗