G-CSF inhibition as a colorectal cancer therapy

G-CSF 抑制作为结直肠癌治疗

• 批准号: 9152355
• 负责人: Ellen J. Beswick
• 金额: $ 34.66万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 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 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9152355
• 关键词: Antibodies; Bone Marrow; CD8B1 gene; CSF3 gene; 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; Risk; Role; Sampling; T cell response; T-Lymphocyte; Testing; Therapeutic; Tissue Sample; Tissues; Tumor Immunity; Tumor Tissue; United States; cancer stem cell; cancer therapy; clinical care; colitis associated cancer; cytokine; cytotoxic; fighting; human tissue; improved; knock-down; macrophage; metastatic colorectal; migration; mortality; mouse model; neoplasm regression; neoplastic cell; neutrophil; new therapeutic target; novel; novel therapeutics; overexpression; prevent; response; stem; 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： 结直肠癌是美国第二大常见癌症原因，具有很高的死亡风险。尽管 新的化疗方案提高了生存率，在美国所有诊断为 CRC 的患者中有 37% 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。 开发新疗法。我们发现，实现这一目标的一种潜在方法是阻断一种关键的细胞因子，该细胞因子 诱导肿瘤细胞增殖和侵袭以及结直肠癌中的抑制性免疫反应。粒细胞 集落刺激因子 (G-CSF) 是 88% 的人类结直肠肿瘤中存在的关键细胞因子。封锁 这种细胞因子在结直肠癌小鼠模型中导致保护性免疫反应的激活 肿瘤消退。 G-CSF 可能诱导调节性 T 细胞积聚并有效抑制细胞毒性细胞 回应。由于这些反应可能具有关键的肿瘤促进功能，我们假设 G-CSF 阻断通过抑制肿瘤进展和诱导抗肿瘤免疫来保护结直肠癌。到 检验该假设，将完成以下具体目标： 具体目标 1：描述 G-CSF/G-CSFR 在结直肠癌进展中的作用及其潜力 封锁作为一种治疗方法。我们假设 G-CSF/G-CSFR 抑制将预防或 消退结直肠癌转移。这将通过敲低肿瘤细胞中的 G-CSF/G-CSFR 来检查， 在肿瘤细胞中过度表达 G-CSF/G-CSFR，并在小鼠模型中采用治疗方法 结直肠癌转移。将检查人类 CRC 组织与 G-CSF/G-CSFR 表达的关联 和转移。 具体目标 2：阐明 G-CSF/G-CSFR 抑制在增强抗肿瘤免疫方面的作用 防止结直肠癌进展。我们假设 G-CSF 诱导肿瘤免疫逃避 通过诱导免疫细胞产生 IL-10 和抑制细胞毒性免疫细胞反应来改善微环境。 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 将检查 NK 和 CD8+ T 细胞上的 G-CSF 以及通过调节 IL-10 的间接影响 将检查肿瘤微环境。 G-CSF抑制NK细胞和CD8+T细胞溶瘤能力 将评估功能。具有高 G-CSF/G-CSFR 与低 G-CSF/G-CSFR 的人类 CRC 和肝转移组织 将检查 NK 和 CD8+ T 细胞活性的表达。 因此，对于这个项目，我们将研究 G-CSF 阻断对肿瘤增殖和 侵袭、激活保护性骨髓和 T 细胞反应，并在侵袭性环境中测试对该通路的阻断 结直肠癌模型和人类肿瘤组织中的转化方法可能会产生新的 结直肠癌的治疗。