CD200R signaling in tumor growth, immunity and immunotherapy

CD200R 信号在肿瘤生长、免疫和免疫治疗中的作用

• 批准号: 10441487
• 负责人: Sujit Basu
• 金额: $ 34.97万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10441487
• 关键词: Adoptive Transfer; Affect; Antibodies; Antibody Therapy; CD 200; Cancer Vaccines; Cells; Dendritic Cells; Dendritic cell tumor; Development; Exhibits; Fc Receptor; Goals; Growth; Human; Immune response; Immunity; Immunocompetent; Immunosuppression; Immunotherapy; Inbred BALB C Mice; Inflammation; Lung; Malignant Neoplasms; Melanoma Cell; Membrane Glycoproteins; Metastatic Neoplasm to the Lung; Modeling; Monoclonal Antibodies; Mus; Myeloid Cells; Myeloid-derived suppressor cells; Neoplasm Metastasis; Pathogenesis; Pathway interactions; Physiological; Play; Receptor Signaling; Regulatory T-Lymphocyte; Role; T cell response; T cell therapy; T-Lymphocyte; Testing; Tumor Antigens; Tumor Immunity; Tumor-associated macrophages; Wild Type Mouse; angiogenesis; antigen-specific T cells; cancer cell; cancer immunotherapy; experimental study; immunological intervention; melanoma; receptor; targeted treatment; tumor; tumor growth; tumor microenvironment; tumor progression

Tumor-associated inflammation and immune responses are key components in the tumor microenvironment (TME) that regulates tumor growth and progression. Tumor-associated myeloid cells (TAMCs) are a group of cells that play not only key roles in inducing tumor-associated inflammation/angiogenesis, but also regulate tumor-specific T cell responses. Thus, identification and characterization of key pathways that can regulate TAMCs are of critical importance for developing cancer immunotherapy. Our recent studies suggest that CD200-CD200 receptor (CD200R) interaction may be important in regulating the TME via affecting TAMCs. We have recently observed that expression of CD200 in melanoma cells significantly inhibits tumor formation and lung metastasis in immune-competent mice. Conversely, mice deficient for CD200R exhibits accelerated growth of CD200-positive tumors. Treatment of mice using an agonistic antibody to CD200R significantly inhibits tumor foci formation in the lungs, suggesting that enhancing CD200R signaling may inhibit tumor growth. The overall goal of this proposal is to elucidate the roles of CD200R signaling in modulating tumor associated inflammation and immunity, and its subsequent contribution to tumor growth and progression. We will also determine if targeting CD200R results in the immune intervention of tumor growth. To achieve these goals, we will first evaluate the development and progression of various CD200-positive tumors in two strains of CD200R-deficient mice. Additionally, we will generate Braf/Pten mice with or without CD200R to evaluate spontaneous melanoma formation, tumor growth, and metastasis (Aim 1). Then, we will evaluate the impacts of CD200R signaling in the induction of tumor-specific T cell responses in the TME of CD200-positive tumors (Aim 2). The establishment of these two steps will pave the way to investigate if targeting CD200R can modulate the TME and if this approach is feasible for cancer immunotherapy (Aim 3). The information generated from these studies will not only help advance our understanding of tumor pathogenesis and immunity, but also provide the rationale for CD200R-targeted immunotherapy of human cancer.

肿瘤相关炎症和免疫反应是肿瘤微环境的关键组成部分 （TME）调节肿瘤的生长和进展。肿瘤相关骨髓细胞 (TAMC) 是一组 细胞不仅在诱导肿瘤相关炎症/血管生成中发挥关键作用，而且还调节 肿瘤特异性 T 细胞反应。因此，可以调节的关键途径的识别和表征 TAMC 对于开发癌症免疫疗法至关重要。我们最近的研究表明 CD200-CD200 受体 (CD200R) 相互作用可能在通过影响 TAMC 来调节 TME 中发挥重要作用。 我们最近观察到黑色素瘤细胞中CD200的表达显着抑制肿瘤形成 和免疫功能正常小鼠的肺转移。相反，缺乏 CD200R 的小鼠表现出加速 CD200阳性肿瘤的生长。使用 CD200R 激动性抗体治疗小鼠效果显着 抑制肺部肿瘤灶形成，表明增强 CD200R 信号传导可能抑制肿瘤 生长。该提案的总体目标是阐明 CD200R 信号在调节肿瘤中的作用 相关的炎症和免疫，及其随后对肿瘤生长和进展的贡献。我们 还将确定靶向 CD200R 是否会导致肿瘤生长的免疫干预。为了实现这些 为了实现目标，我们将首先评估两种毒株中各种CD200阳性肿瘤的发生和进展 CD200R 缺陷小鼠。此外，我们将生成带有或不带有 CD200R 的 Braf/Pten 小鼠来评估 自发黑色素瘤形成、肿瘤生长和转移（目标 1）。然后，我们将评估影响 CD200R 信号传导在 CD200 阳性肿瘤 TME 中诱导肿瘤特异性 T 细胞反应的作用 （目标 2）。这两个步骤的建立将为研究针对 CD200R 是否可以 调节 TME 以及这种方法是否适用于癌症免疫治疗（目标 3）。信息 这些研究产生的结果不仅有助于增进我们对肿瘤发病机制的理解， 免疫，也为人类癌症的 CD200R 靶向免疫治疗提供了理论基础。