Local Immuroregulation of Cutaneous Carcinogenesis

 描述（由申请人提供）：非黑色素瘤皮肤癌（NMSC）、基底细胞癌（BCC）和鳞状细胞癌（SCC）是角质形成细胞衍生的恶性肿瘤，共同构成了美国最常见的癌症形式。SCC由受损的表皮基底和毛囊漏斗角化细胞（KC）引起，最常首先演变成癌前光化性角化病（AK），影响超过5000万美国人。慢性紫外线B（UVB）暴露已被认为是AK和SCC发展的主要环境风险因素，这两种类型的肿瘤在主细胞周期调节因子p53基因中携带频繁突变。我们最近阐明了一个关键的，完全不可预见的，作用朗格汉斯细胞（LC）在皮肤癌的发生，明确表明，LC发挥重大影响，刺激KC的遗传毒性，以及促进肿瘤的促进。根据我们的假设，LC作为检测器的物理和化学表皮扰动，并提供效应器功能的刺激KC遗传毒性（标志转化）和增殖和去分化（发育异常和突变克隆扩张的标志）。我们已经设计了新的范例LC调节的表皮应激反应和IL-22产生的先天淋巴（ILC）细胞UVB诱导的致癌作用。对于生理性表皮扰动的条件，在该构建体下，LC准备检测和响应角质形成细胞损伤，从角质形成细胞中引发精确的局部响应。然而，当这种表皮扰动导致DNA损伤暴露（例如化学诱变剂、紫外线辐射），导致KC获得沉默肿瘤抑制基因和/或组成性激活癌基因以支持增殖和抗凋亡的突变时，突变KC的克隆扩增被激活。以这种方式，肿瘤促进篡夺了LC的正常生理反应，并且慢性UVB暴露和应激KC刺激LC产生驱动KC转化和突变克隆扩增的因子。我们已经在多种皮肤癌发生模型中表明，这些活性对皮肤癌发生率的净效应， 克隆形成、克隆扩增和最终的肿瘤生长明确地依赖于LC的存在，我们在此提出鉴定潜在的机制并开始以它们为靶点进行预防性治疗。为了实现这一目标，我们将致力于以下具体目标：（1）阐明支持LC促进慢性UVB诱导的皮肤癌发生的效应器机制;（2）确定介导LC促进慢性UVB诱导的皮肤癌发生的关键传感器组件;（3）研究预防性抑制LC介导的机制，促进皮肤恶性肿瘤的潜力。为了帮助实现这些目标，我们已经开发了一种创新的策略，选择性的再生LC从富含hepatosor-rich胎儿组织，这将使我们能够充分阐明LC促进慢性UVB诱导的角质形成细胞的遗传毒性，表皮增殖和去分化，和突变p53 KC克隆扩张的机制。

 DESCRIPTION (provided by applicant): Non-melanoma skin cancers (NMSCs), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are keratinocyte-derived malignancies that together comprise the most prevalent form of cancer in the US. SCCs arise from damaged epidermal basal and folliculo-infundibular keratinocytes (KC), most often evolving first into pre-cancerous actinic keratoses (AKs) that affect over 50 million Americans. Chronic ultraviolet B (UVB) light exposure has been implicated as the major environmental risk factor for development of AK and SCC, with both types of neoplasm harboring frequent mutations in the master cell cycle regulator p53 gene. We recently elucidated a critical, entirely unforeseen, role for Langerhans cells (LC) in cutaneous carcinogenesis, definitively demonstrating that LC exert major influences in both stimulating KC genotoxicity as well as facilitating tumor promotion. Under our hypothesis, LC act as detectors of physical and chemical epidermal perturbation and provide effector functions for the stimulation of KC genotoxicity (the hallmark transformation) and proliferation and dedifferentiation (the hallmarks of dysplasia and mutant clonal expansion). We have devised novel paradigms relating LC regulation of the epidermal stress response and IL-22-producing innate lymphoid (ILC) cells to UVB-induced carcinogenesis. For conditions of physiologic epidermal perturbation, under this construct, LC are poised to detect and respond to keratinocyte damage, eliciting from them precise, localized responses. However, when such epidermal perturbation leads to DNA-damaging exposure (e.g. chemical mutagen, ultraviolet radiation), resulting in KC acquisition of mutations that silence tumor-suppressor genes and/or constitutively activate oncogenes to support proliferation and resistance to apoptosis, a clonal expansion of the mutated KC ensues. In this way, tumor promotion usurps the normal physiologic response of LC, and chronic UVB exposure and stressed KCs stimulate LC to produce factors that drive KC transformation and mutant clonal expansion. We have shown in multiple models of cutaneous carcinogenesis that the net effect of these activities on the rates of clonal formation, clonal expansion and eventual tumor outgrowth are unequivocally dependent on the presence of LC, and we herein propose to identify the underlying mechanisms and begin to target them translationally. Toward this goal, we will pursue the following specific aims: (1) Elucidate the effector mechanisms underpinning LC facilitation of chronic UVB-induced cutaneous carcinogenesis; (2) Identify the key sensor components mediating LC facilitation of chronic UVB-induced cutaneous carcinogenesis; and (3) Investigate the potential to translationally inhibit LC-mediated mechanisms that facilitate cutaneous malignancy. To help accomplish these aims, we have developed an innovative strategy for the selective repopulation of LCs from precursor-rich fetal tissues that will enable us to fully elucidate the mechanisms by which LC facilitate chronic UVB-induced keratinocyte genotoxicity, epidermal proliferation and dedifferentiation, and mutant p53 KC clonal expansion.