G-CSF inhibition as a colorectal cancer therapy

项目总结： 在美国，结直肠癌是第二大常见致癌原因，具有很高的死亡率。而当 新的化疗方案提高了存活率，在美国所有被诊断为结直肠癌的患者中有37% 各州将死于这种疾病。显然，需要新的肿瘤靶点来开发改进的治疗方法。 接近了。利用天然的抗肿瘤免疫是开发新疗法的一种很有前途的方法。 开发新的治疗方法。我们已经发现，一个潜在的方法是通过阻断一种关键的细胞因子来实现这一点 诱导结直肠癌肿瘤细胞增殖和侵袭，并抑制免疫反应。粒细胞 集落刺激因子(G-CSF)是一种关键的细胞因子，存在于88%的人类大肠肿瘤中。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和 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细胞 回应。由于这些反应可能具有关键的促癌功能，我们假设G-CSF 阻滞剂通过抑制肿瘤进展和诱导抗肿瘤免疫，对结直肠癌具有保护作用。至 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及其潜在的作用 将封锁作为一种治疗方法。我们假设抑制G-CSF/G-CSFR将阻止或 减少结直肠癌转移。这将通过下调肿瘤细胞中的G-CSF/G-CSFR来进行检测， 在肿瘤细胞中过表达G-CSF/G-CSFR，并在小鼠模型中采用治疗方法 结直肠癌转移。将检查人类结直肠癌组织与G-CSF/G-CSFR表达的相关性 和转移。 特异性目标2：阐明G-CSF/G-CSFR抑制在增强抗肿瘤免疫中的作用 防止CRC进展。我们假设G-CSF诱导肿瘤免疫逃避 微环境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。 将检测G-CSF对髓系细胞和T细胞产生IL-10的直接影响。的直接影响 将检测G-CSF对NK和CD8+T细胞的影响以及通过调节IL-10在体内的间接作用。 将检查肿瘤微环境。G-CSF对NK细胞和CD8+T细胞肿瘤杀伤的抑制作用 将对功能进行评估。高G-CSF/G-CSFR与低G-CSF/G-CSFR的人结直肠癌和肝转移癌组织 表达将检测NK和CD8+T细胞活性。 因此，在这个项目中，我们将研究G-CSF阻断肿瘤增殖和 侵袭、激活保护性髓系和T细胞反应，并在侵袭性试验中阻断这一途径 在结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 结直肠癌的治疗。

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.