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

基本信息

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
项目类别：
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

项目摘要

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.

肿瘤相关的炎症和免疫反应是肿瘤微环境中的关键组成部分（TME）调节肿瘤生长和进展。肿瘤相关的髓样细胞（TAMC）是一组不仅在诱导肿瘤相关的炎症/血管生成中起关键作用的细胞，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对于发展癌症免疫疗法至关重要。我们最近的研究表明 CD200-CD200受体（CD200R）相互作用对于通过影响TAMC来调节TME可能很重要。我们最近观察到，黑色素瘤细胞中CD200的表达显着抑制了肿瘤的形成免疫能力小鼠中的肺转移。相反，缺乏CD200R的小鼠表现出加速 CD200阳性肿瘤的生长。使用CD200R的激动抗体对小鼠进行处理抑制肺部肿瘤灶的形成，表明增强CD200R信号可能会抑制肿瘤生长。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力及其随后对肿瘤生长和进展的贡献。我们还将确定靶向CD200R是否导致肿瘤生长的免疫干预。实现这些目标，我们将首先评估两种菌株中各种CD200阳性肿瘤的发育和发展 CD200R缺陷小鼠的。此外，我们将生成带有或没有CD200R的BRAF/PTEN小鼠来评估自发的黑色素瘤形成，肿瘤生长和转移（AIM 1）。然后，我们将评估影响 CD200R信号传导在CD200阳性肿瘤TME中的肿瘤特异性T细胞反应中的诱导（目标2）。建立这两个步骤将为调查CD200R是否可以铺平道路调节TME，如果这种方法对于癌症免疫疗法是可行的（AIM 3）。信息这些研究产生的不仅将有助于我们对肿瘤发病机理和免疫力，但也为人类癌症的CD200R靶向免疫疗法提供了理由。