CSF1 Receptor-Mediated Tumor Microenvironment in Lung Cancer

CSF1 受体介导的肺癌肿瘤微环境

• 批准号: 9888672
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888672
• 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; Ultrasonography; anti-cancer; arm; base; cancer immunotherapy; cancer therapy; chemokine; clinical material; conditional knockout; cytokine; exoenzyme; extracellular; genetic analysis; immune function; immunogenic; inhibitor/antagonist; 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

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， 其免疫学研究在治疗肺结核方面取得了临床和科学上的突破 癌在这里，我们召集了一个杰出的研究团队，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骨髓细胞的作用 如巨噬细胞和树突状细胞（DC），并寻求一种新的方法， 介导的癌症免疫疗法。微环境决定了 骨髓细胞我们的实验室报告，集落刺激因子1（CSF 1），一个关键的介质， 微环境的变化对于确定DC亚群的免疫功能至关重要。它有 众所周知，肿瘤细胞分泌CSF 1来改变其微环境，然而， 作用机制尚未完全阐明。几种靶向CSF 1受体（CSF 1 R）的药物 正在进行的临床试验中接受癌症治疗测试。我们提出了肿瘤的新作用- 产生CSF 1，改变肿瘤免疫微环境，使肿瘤进展， 产生自分泌运动因子（ATX），该自分泌运动因子（ATX）增加前肿瘤髓样细胞的数量， 巨噬细胞和DC。ATX，也称为溶血磷脂酶D，是细胞外分泌的 并酶促产生溶血磷脂酸（LPA）， 体液中的磷脂众所周知，LPA刺激细胞增殖、迁移和增殖。 髓系细胞的存活率。 该提案基于PI在骨髓细胞生物学方面的两个新的关键发现：（1）ATX 在CSF 1及其受体（CSF 1 R）的控制下，在骨髓细胞中高度表达 （2）ATX调节肺髓样细胞的居住群体的大小， CSF 1 R依赖性方式（CSF 1 R-ATX途径）。这些发现共同导致了 假设肿瘤产生的CSF 1刺激前肿瘤髓样细胞分泌ATX， 以增加肿瘤前巨噬细胞和DC的数量。为了验证这个假设， 我们提出三个具体目标。基础科学部门将采用这些方法来证明- 通过利用具有靶基因的缺失或过量的新型转基因小鼠， 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。 采用最先进的纳米递送技术在肺癌小鼠模型中的CSF 1 R-ATX通路 系统 通过使用CSF 1 R-ATX通路特异性的新型转基因小鼠， 患者和创新的方法，我们将询问肿瘤中的CSF 1 R-ATX通路， 浸润性骨髓细胞，在肿瘤细胞生物学中起关键作用，并可能导致肿瘤细胞的凋亡。 肺癌的新治疗策略的开发。