Regulation of immune privilege in metastatic squamous cell carcinoma

描述(申请人提供)：鳞状细胞癌(SCC)是一种起源于表皮的非黑色素瘤皮肤癌，是人类最常见的恶性肿瘤之一。SCC的特点是具有很高的侵袭和转移倾向，并且可能是致命的。鳞状细胞癌发病机制的分子机制已被积极研究，然而，除了手术外，没有任何预防或治疗策略成功地针对这种病变。CD200，也被称为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对髓系细胞功能的抑制。CD200在致癌角质形成细胞中的诱导作用已有报道；然而，CD200在其他正常皮肤上皮细胞中对SCC发病的起始和过程的影响尚不清楚。我们的初步发现表明，CD200的诱导是小鼠和人类皮肤SCC转移到淋巴结的标志，CD200阳性的转移性角质形成细胞似乎直接与CD200R阳性的髓样细胞(CD11b+)相互作用，这表明SCC细胞的迁移可能依赖于它们直接抑制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确定CD200在皮肤鳞状细胞癌形成和转移中的作用。我们将验证CD200通过直接抑制CD200R阳性髓系细胞的抗肿瘤功能来调节皮肤SCC转移能力的假设。为了验证这一假设，我们将确定皮肤鳞状细胞癌和鳞状细胞癌来源的淋巴转移中CD200和CD200R阳性细胞的所有亚型，以全面描述可能有助于转移性SCC免疫豁免的CD200-CD200R细胞相互作用。我们将在一个转基因小鼠模型中评估CD200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，我们将去除转移的SCC细胞中的CD200，并评估其对髓系细胞活性和体内CD200缺陷的SCC细胞重建淋巴转移的能力的影响。准确定位免疫和转移SCC细胞之间的这些关键相互作用的能力将提供对癌症免疫机制的更好洞察，并导致对这些潜在致命癌症的更有效的治疗策略。公共卫生相关性：各种癌症的转移过程已经有了很好的记录；然而，尽管目前取得了进展，转移性癌症仍然占到了几乎所有与实体肿瘤有关的死亡。这项提议旨在识别赋予癌细胞免疫豁免权并刺激转移过程的某些分子，希望引入新的靶点来推进这种致命疾病的临床治疗。

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.