CSF1 Receptor-Mediated Tumor Microenvironment in Lung Cancer

CSF1 受体介导的肺癌肿瘤微环境

• 批准号: 10376736
• 负责人: Gye Young Park
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376736
• 关键词: Adopted; Anabolism; Attenuated; Basic Science; Binding; Biochemical; Biopsy; Body Fluids; CSF1 gene; Cancer Biology; Cancer Etiology; Cancer Model; Cell Lineage; Cell Proliferation; Cells; Cellular biology; Cessation of life; Chemotaxis; Clinical; Clinical Trials; Cytometry; Data; Dendritic Cells; Development; Encapsulated; Genes; Human; Immune; Immune system; Immunologics; Immunologist; Inhalation; Knockout Mice; Lead; Lung; Lung Adenocarcinoma; Lysophospholipase; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Mediator of activation protein; Mouse Strains; Mus; Mutation; Myelogenous; Myeloid Cells; Nano delivery; Oncologist; Outcome; Pathway interactions; Patient Recruitments; Patients; Phenotype; Phospholipids; Play; Population; Progression-Free Survivals; Prospective Studies; Receptor Activation; Receptor Cell; Receptor Gene; Receptor Inhibition; Reporting; Research; Research Personnel; Role; Sampling; Stimulus; System; Tamoxifen; Techniques; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Tissues; Transgenic Mice; Tumor Biology; Tumor Cell Biology; Tumor-infiltrating immune cells; anti-cancer; arm; base; cancer immunotherapy; cancer therapy; chemokine; clinical material; conditional knockout; cytokine; exoenzyme; extracellular; genetic analysis; immune function; immunogenic; inhibitor; innovation; lysophosphatidic acid; macrophage; migration; mortality; mouse model; neoplastic cell; novel; novel strategies; novel therapeutic intervention; paracrine; receptor; targeted agent; transcriptome sequencing; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions; ultrasound

Thanks to the collaborative efforts of immunologists and oncologists, cancer immunotherapy and its immunologic research made clinical and scientific breakthrough in treatment of lung cancer. Here, we assembled an outstanding team of researchers including immunologist, clinical oncologists, and cancer biologist to investigate the role of tumor-infiltrating myeloid cells such as macrophages and dendritic cells (DCs), and seek a new approach for myeloid cell- mediated cancer immunotherapy. Microenvironmental milieu determines the phenotype of myeloid cells. Our lab reported that Colony Stimulating Factor 1 (CSF1), one of key mediators of microenvironment, is critical for determining the immunologic function of a DC subset. It has been well known that tumor cells secrete CSF1 to alter their microenvironment and yet, the mechanism of action is not fully elucidated. Several agents targeting CSF1 receptor (CSF1R) are being tested for cancer treatment in ongoing clinical trials. We propose a new role of tumor- produced CSF1 in altering tumor immune microenvironment toward tumor progression by producing autotaxin (ATX) which increases the number of protumoral myeloid cells such as macrophages and DCs. ATX, also known as lysophospholipase D, is secreted extracellularly and enzymatically generates lysophosphatidic acid (LPA) which is the most abundant phospholipid in body fluid. LPA is well known to stimulate cellular proliferation, migration and survival for myeloid lineage cells. The proposal is based on the PI’s two new critical discoveries on myeloid cell biology; (1) ATX is highly expressed in myeloid cells under the control of CSF1 and its receptor (CSF1R) activation, (2) ATX regulates the size of the residential population of lung myeloid cells in the CSF1R-dependent manner (CSF1R-ATX pathway). Together these findings have led to the hypothesis that tumor-produced CSF1 stimulates protumoral myeloid cells to secrete ATX in order to increase the number of protumoral macrophages and DCs. To validate the hypothesis, we propose three specific aims. The basic science arm will employ the approaches for proof-of- concept by utilizing the novel transgenic mice that have the loss or excess of the target genes. The clinical arm will exploit clinical samples from patients with lung cancer to verify the proof-of- concept. Lastly, in the translational arm, we will examine the therapeutic potentials of interfering CSF1R-ATX pathway in the mouse model of lung cancer by adopting state-of-art nano-delivery system. By using novel transgenic mice specific to CSF1R-ATX pathway, the clinical materials from patients and innovative approaches, we will interrogate the CSF1R-ATX pathway in tumor- infiltrating myeloid cells, which play a key role in tumor cell biology and could lead to the development of a new therapeutic strategy for lung cancer.

由于免疫学家和肿瘤学家的共同努力，癌症免疫治疗 其免疫学研究在治疗肺部疾病方面取得了临床和科学上的突破 癌症。在这里，我们聚集了一支优秀的研究团队，包括免疫学家， 临床肿瘤学家和癌症生物学家研究肿瘤浸润性髓系细胞的作用 如巨噬细胞和树突状细胞(DC)，为髓系细胞寻找新的途径 介导性癌症免疫治疗。微环境决定了其表型 髓系细胞。我们的实验室报道，集落刺激因子1(CSF1)是人类免疫缺陷的关键介质之一。 微环境是决定DC亚群免疫功能的关键。它有 众所周知，肿瘤细胞分泌CSF1来改变其微环境，然而， 其作用机制尚未完全阐明。几种靶向CSF1受体(CSF1R)的药物 正在进行的临床试验中正在进行癌症治疗测试。我们提出了肿瘤的新角色-- 产生CSF1通过改变肿瘤免疫微环境促进肿瘤进展 产生自体趋化素(ATX)，增加前肿瘤髓系细胞的数量，如 巨噬细胞和DC。ATX，也称为溶血磷脂酶D，由细胞外分泌 并通过酶作用产生溶血磷脂酸(LPA)，这是最丰富的 体液中的磷脂。众所周知，LPA可以刺激细胞增殖、迁移和 髓系细胞的存活率。 这项建议是基于PI在髓系细胞生物学方面的两项新的关键发现：(1)ATX 在CSF1及其受体(CSF1R)调控下，在髓系细胞中高表达 激活，(2)ATX调节肺髓系细胞居留群体的大小 CSF1R依赖方式(CSF1R-ATX途径)。这些发现加在一起导致了 肿瘤产生的CSF1刺激前列腺癌髓系细胞分泌ATX的假说 以增加肿瘤前巨噬细胞和DC的数量。为了验证这一假设， 我们提出了三个具体目标。基础科学部门将采用以下方法来证明- 通过利用具有丢失或过量目的基因的新型转基因小鼠来进行概念。 临床部门将利用肺癌患者的临床样本来验证- 概念。最后，在平移臂中，我们将检查干扰的治疗潜力 采用最新的纳米递送技术在小鼠肺癌模型中的CSF1R-ATX通路 系统。 通过使用针对CSF1R-ATX途径的新型转基因小鼠，来自 患者和创新的方法，我们将询问肿瘤中的CSF1R-ATX通路- 浸润性髓系细胞，在肿瘤细胞生物学中发挥关键作用，可能导致 开发肺癌的新治疗策略。