CD200R signaling in tumor growth, immunity and immunotherapy

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)调节肿瘤的生长和发展肿瘤相关骨髓细胞（TAMCs）是一组 这些细胞不仅在诱导肿瘤相关炎症/血管生成中起关键作用，而且还调节 肿瘤特异性T细胞应答。因此，识别和表征可以调节 TAMCs对于开发癌症免疫疗法至关重要。我们最近的研究表明， CD 200-CD 200受体（CD 200 R）相互作用可能通过影响TAMCs在调节TME中起重要作用。 我们最近观察到在黑色素瘤细胞中表达CD 200显著抑制肿瘤形成， 和肺转移。相反，缺乏CD 200 R的小鼠表现出加速的 CD 200阳性肿瘤的生长。使用针对CD 200 R的激动性抗体治疗小鼠， 抑制肺中肿瘤灶的形成，这表明增强CD 200 R信号传导可以抑制肿瘤的发生。 增长本研究的总体目标是阐明CD 200 R信号转导在调节肿瘤中的作用。 相关的炎症和免疫，以及其随后对肿瘤生长和进展的贡献。我们 还将确定靶向CD 200 R是否会导致肿瘤生长的免疫干预。实现这些 为了达到这一目的，我们将首先评估两种菌株中各种CD 200阳性肿瘤的发生和进展 CD 200 R缺陷的小鼠。此外，我们将产生具有或不具有CD 200 R的Braf/Pten小鼠以评估 自发性黑色素瘤形成、肿瘤生长和转移（目的1）。然后，我们将评估 在CD 200阳性肿瘤的TME中诱导肿瘤特异性T细胞应答的CD 200 R信号传导 (Aim 2）。这两个步骤的建立将为研究靶向CD 200 R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）。的信息 这些研究产生的结果不仅有助于我们进一步了解肿瘤的发病机制， 本发明的目的不仅在于增强免疫力，而且还为人类癌症的CD 200 R靶向免疫疗法提供了理论基础。

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.