Regulation of immune privilege in metastatic squamous cell carcinoma

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。SCCs的特点是具有侵袭和转移的高倾向，可能是致命的。SCC发病机制的分子事件已被积极研究；然而，除了手术之外，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髓细胞功能的抑制。在致瘤性角化细胞中有CD200诱导的报道；然而，CD200在其他正常上皮中对SCC发病的发生和过程的影响尚不清楚。我们的初步研究结果表明，诱导CD200是小鼠和人类皮肤SCC转移到淋巴结的标志，CD200阳性转移性角化细胞似乎直接与cd200r阳性骨髓（CD11b+）细胞相互作用，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。总的来说，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阳性骨髓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，我们将在皮肤鳞状细胞癌和鳞状细胞源性淋巴结转移中鉴定所有CD200和cd200r阳性细胞亚型，以充分表征可能导致转移性鳞状细胞癌免疫特权的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，该模型在强力霉素的控制下将CD200靶向到表皮的增殖层。最后，我们将在转移性SCC细胞中切除CD200，并评估其对骨髓细胞活性的影响，以及CD200缺陷SCC细胞在体内重建淋巴结转移的能力。确定免疫和转移性SCC细胞之间这些关键相互作用的能力将为癌症免疫机制提供更好的见解，并为这些潜在致命的癌症提供更有效的治疗策略。公共卫生相关性：各种癌症的转移过程已被充分记录；然而，尽管目前取得了进展，但转移性癌症仍然占几乎所有与实体瘤相关的死亡。这项提议旨在确定某些赋予癌细胞免疫特权的分子，并刺激转移过程，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.