Regulation of immune privilege in metastatic squamous cell carcinoma

转移性鳞状细胞癌免疫豁免的调节

• 批准号: 7643837
• 负责人: DAVID M OWENS
• 金额: $ 25.25万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7643837
• 关键词: Ablation; Accounting; CD 200; Cell Communication; Cell physiology; Cells; Cessation of life; Clinical Treatment; Cutaneous; Data; Development; Disease; Disseminated Malignant Neoplasm; Doxycycline; Epidermis; Epigenetic Process; Epithelium; Event; Exhibits; Generations; Glycoproteins; Human; ITGAM gene; Immune; Immunity; Immunosuppressive Agents; Lead; Lesion; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Membrane Glycoproteins; Metastatic Neoplasm to Lymph Nodes; Metastatic Squamous Cell Carcinoma; Molecular; Mus; Myelogenous; Myeloid Cells; Neoplasm Metastasis; Operative Surgical Procedures; Pathogenesis; Population; Prevention; Process; Regulation; Reporting; Research; Role; Skin; Skin Carcinoma; Solid Neoplasm; Squamous cell carcinoma; Surface; Testing; Therapeutic; Tissues; Transgenic Mice; Transgenic Organisms; base; cancer cell; design; in vivo; insight; keratinocyte; lymph nodes; metastatic process; migration; mouse model; novel; public health relevance; receptor; reconstitution; response; skin squamous cell carcinoma; transgene expression; tumor; tumorigenic

DESCRIPTION (provided by applicant): Squamous cell carcinoma (SCC) is a type of nonmelanoma skin cancer derived from the epidermis and is one of the most frequent human malignancies. SCCs characteristically exhibit a high propensity for invasion and metastasis and may be lethal. The molecular events underlying the pathogenesis of SCC have been actively studied; however, no resulting preventative or therapeutic strategies, apart from surgery, have successfully targeted this lesion. CD200, also referred as OX-2, is a widely expressed type I transmembrane glycoprotein that is thought to primarily mediate the suppression of myeloid cell function through its receptor, CD200R, in various tissues including the skin. CD200 induction has been reported in tumorigenic keratinocytes; however, the impact of CD200 in otherwise normal epithelium on the initiation and course of SCC pathogenesis is unknown. Our preliminary findings show that induction of CD200 is a hallmark of both murine and human cutaneous SCC metastasis to the lymph node and that CD200-positive metastatic keratinocytes appear to directly interact with CD200R-positive myeloid (CD11b+) cells indicating that the migration of SCC cells may be dependent on their ability to directly suppress the anti-tumor responses of CD200R-positive immune cells. Overall, the studies outlined in this proposal are aimed at defining the role of CD200 in cutaneous SCC formation and metastasis. We will test the hypothesis that CD200 regulates the metastatic capacity of cutaneous SCC by directly suppressing the anti-tumor function of CD200R-positive myeloid cells. To test this hypothesis, we will identify all subtypes of CD200 and CD200R-positive cells in cutaneous SCC and SCC-derived lymph node metastases in order to fully characterize the putative CD200-CD200R cell interactions that may contribute to metastatic SCC immune privilege. We will assess the capacity of CD200 to stimulate SCC formation and metastasis in a transgenic mouse model that targets CD200 to the proliferative layer of the epidermis under the control of doxycycline. Finally, we will ablate CD200 in metastatic SCC cells and assess its impact on myeloid cell activity and the ability of CD200-deficient SCC cells to reconstitute lymph node metastases in vivo. The ability to pinpoint these critical interactions between immune and metastatic SCC cells will provide better insight into the mechanisms of cancer immunity and lead to more effective therapeutic strategies for these potentially fatal cancers. PUBLIC HEALTH RELEVANCE: The process of metastasis has been well documented for a wide variety of cancers; however, despite current progress metastatic cancers still account for almost all of the deaths related to solid tumors. This proposal aims to identify certain molecules that bestow immune privilege on cancer cells and stimulate the metastatic process with the hope of introducing new targets to advance clinical treatment of this lethal disease.

描述（由申请人提供）：鳞状细胞癌（SCC）是一种源自表皮的非黑色素瘤皮肤癌，是最常见的人类恶性肿瘤之一。 鳞状细胞癌的特点是表现出高度的侵袭和转移倾向，并且可能是致命的。 SCC 发病机制背后的分子事件已得到积极研究；然而，除了手术之外，没有任何预防或治疗策略能够成功地针对这种病变。 CD200，也称为 OX-2，是一种广泛表达的 I 型跨膜糖蛋白，被认为主要通过其受体 CD200R 在包括皮肤在内的各种组织中介导骨髓细胞功能的抑制。 据报道，CD200 在致瘤性角质形成细胞中被诱导；然而，正常上皮中的 CD200 对鳞状细胞癌发病机制的起始和进程的影响尚不清楚。 我们的初步研究结果表明，CD200 的诱导是小鼠和人皮肤鳞状细胞癌淋巴结转移的标志，并且 CD200 阳性转移性角质形成细胞似乎与 CD200R 阳性骨髓 (CD11b+) 细胞直接相互作用，表明鳞状细胞癌细胞的迁移可能取决于它们直接抑制 CD200R 阳性免疫细胞的抗肿瘤反应的能力。 总体而言，本提案中概述的研究旨在明确 CD200 在皮肤 SCC 形成和转移中的作用。 我们将检验 CD200 通过直接抑制 CD200R 阳性骨髓细胞的抗肿瘤功能来调节皮肤鳞状细胞癌的转移能力的假设。 为了检验这一假设，我们将鉴定皮肤 SCC 和 SCC 衍生淋巴结转移中 CD200 和 CD200R 阳性细胞的所有亚型，以便充分表征可能有助于转移性 SCC 免疫特权的推定 CD200-CD200R 细胞相互作用。 我们将评估 CD200 在转基因小鼠模型中刺激鳞状细胞癌形成和转移的能力，该模型在多西环素的控制下将 CD200 靶向表皮增殖层。 最后，我们将消除转移性 SCC 细胞中的 CD200，并评估其对骨髓细胞活性的影响以及 CD200 缺陷的 SCC 细胞在体内重建淋巴结转移的能力。 查明免疫细胞和转移性鳞状细胞癌之间这些关键相互作用的能力将有助于更好地了解癌症免疫机制，并为这些潜在致命的癌症制定更有效的治疗策略。 公共健康相关性：多种癌症的转移过程已得到充分记录；然而，尽管目前取得了进展，转移性癌症仍然占实体瘤相关死亡的几乎全部。 该提案旨在识别某些赋予癌细胞免疫特权并刺激转移过程的分子，希望引入新的靶点来推进这种致命疾病的临床治疗。