Defining the role of innate immune cells in the early stages of immune surveillance of skin cancer by using a novel model that allows in vivo imaging of the immunoediting process.

通过使用允许对免疫编辑过程进行体内成像的新模型，定义先天免疫细胞在皮肤癌免疫监视早期阶段的作用。

• 批准号: 10704126
• 负责人: Dennis Roop
• 金额: $ 50.87万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704126
• 关键词: Academia; Address; Biopsy; Cells; Chimeric Proteins; Confocal Microscopy; Data; Development; Early Diagnosis; Engineering; Epidermis; Epithelium; Equilibrium; Event; Generations; Genomics; Growth; Hair Removal; Hair follicle structure; Human; Immune; Immune Evasion; Immune system; Immunity; Immunocompetent; Immunologic Monitoring; Immunologic Surveillance; Immunology procedure; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Situ; Individual; Industry; Intervention; Lesion; Lymphoid Cell; Maintenance; Malignant Neoplasms; Measurable; Mediating; Mesenchymal; Methods; Modeling; Molecular; Multiplexed Ion Beam Imaging; Mus; Natural Killer Cells; Neoplasms; Normal tissue morphology; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Play; Prevention; Process; Protein Engineering; Resistance development; Resolution; Risk; Role; Skin; Skin Cancer; System; Techniques; Testing; Time; Tissue Model; Transforming Growth Factor beta; Transplantation; Tumor Escape; Tumor Immunity; Up-Regulation; Visual; Visualization; Waxes; anti-PD-L1; cancer cell; cancer immunotherapy; cancer prevention; cancer therapy; candidate identification; candidate marker; carcinogenesis; cell transformation; differential expression; drug efficacy; drug testing; experimental study; high risk; immunosuppressed; in vivo; in vivo imaging; keratinocyte; mouse model; neglect; non-invasive imaging; novel; organ transplant recipient; potential biomarker; prevent; resistance mechanism; screening; transcriptomics; tumor; tumor growth

An understanding of cancer immune evasion has recently led to revolutionary immunotherapies and a subsequent rush, by both industry and academia, to identify additional mechanisms of immune suppression employed by cancer cells. Since these efforts rely on models of full-fledged cancer, there remains a neglected opportunity to target neoplasms prior to the development of immune evasive character. The lack of models for tracing de novo somatic transformation in vivo has prevented direct characterization of early carcinogenesis, including the first interactions with immune cells. To address this deficiency, a novel mouse model has been developed, which allows fluorescent tracing of individual transformed clones in the skin. A special transplant technique has been used to integrate fluorescent, transformation-inducible keratinocytes into the epidermis of an immunocompetent mouse, where they generate isolated, homeostatic clones. These colonies can be non- invasively imaged at subcellular resolution via intravital confocal microscopy as transformation is induced. This technique provides the first-ever direct visualization of cancer development in situ. Since immunity represents a pivotal barrier to the successful outgrowth of neoplasms, this model was engineered to allow visualization of immune cells, as well. The concept of immunoediting provides a framework for how cancers evolve immune- evasive strategies during their development. Immunoediting includes a prolonged dormancy, termed the “equilibrium phase”, during which immunity prevents tumor outgrowth without destroying the transformed cells. For the first time, this model allows the observation of all three phases of immunoediting: elimination, equilibrium, and escape, and reveals that the normal tissue microenvironment plays a central role in early immune evasion. This novel model also reveals a role for innate immune cells in the early stages of immune surveillance of skin cancer and in the maintenance of the equilibrium phase. During the equilibrium phase, transformed cells may be uniquely sensitive to interventions since their lower numbers and relative homogeneity will hinder development of resistance mechanisms. The ability to visualize de novo transformation in this model allows this hypothesis to be tested. In addition, this model will allow the characterization of mechanisms that mediate the hidden events of immunoediting. New preliminary data reveal that the transition from equilibrium lesions to escape tumors involves the upregulation of TGFβ3 in escape tumors, which concurrently undergo epithelial-mesenchymal transition. The increased levels of TGFβ3 convert NK cells, that can inhibit tumor growth, into intermediate type 1 innate lymphoid cells that cannot inhibit tumor growth. This revised application will further pursue both cellular and molecular mechanisms suggested by these preliminary data. Finally, the ability to visualize immune-mediated dormant lesions may uncover potential biomarkers, which might be translatable for early detection in high-risk human patients, such as immunosuppressed organ transplant recipients, who have a 100-fold increased risk of developing skin cancer.

对癌症免疫逃避的理解最近导致了革命性的免疫疗法和 随后，工业界和学术界争先恐后地寻找其他免疫抑制机制 受雇于癌细胞。由于这些努力依赖于完全成熟的癌症模型，因此仍然存在一个被忽视的 在免疫回避特征形成之前，有机会瞄准肿瘤。模型的缺乏 在体内追踪新的体细胞转化阻止了对早期癌变的直接表征， 包括与免疫细胞的第一次互动。为了解决这一缺陷，一种新的老鼠模型已经被 开发的，它允许对皮肤中的单个转化克隆进行荧光跟踪。一次特殊的移植 技术已经被用来将荧光的、转化诱导的角质形成细胞整合到 一种具有免疫功能的小鼠，在那里它们会产生孤立的、自我平衡的克隆。这些殖民地可以是非 在诱导转化时，通过活体共聚焦显微镜以亚细胞分辨率进行侵入性成像。这 这项技术提供了有史以来第一次直接的原位癌症发展可视化。因为豁免权代表 作为肿瘤成功生长的关键屏障，这个模型被设计成允许可视化 免疫细胞也是如此。免疫编辑的概念为癌症如何进化免疫提供了一个框架- 在其发展过程中的规避策略。免疫编辑包括一种延长的休眠，称为 “平衡阶段”，在此期间，免疫可以防止肿瘤生长，而不会破坏转化的细胞。 这个模型第一次允许观察免疫编辑的所有三个阶段：消除， 平衡和逃逸，并揭示了正常组织微环境在早期起着中心作用 免疫逃避。这个新的模型还揭示了先天免疫细胞在免疫早期阶段的作用。 监测皮肤癌和维持平衡期。在平衡阶段， 转化的细胞可能对干预特别敏感，因为它们的数量较少，而且相对 同质性将阻碍抗性机制的发展。想象从头开始的能力 这一模型中的变换使这一假设得以检验。此外，该模型将允许 对调节免疫编辑隐藏事件的机制进行表征。新的初步数据显示 从平衡性病变到逃逸肿瘤的转变与逃逸过程中转化生长因子β-3的上调有关 肿瘤，同时经历上皮-间充质转化。转化生长因子β-3水平的升高 能抑制肿瘤生长的NK细胞转化为不能抑制肿瘤的中间型先天淋巴样细胞 成长。这一修订后的应用程序将进一步探索由 这些初步数据。最后，可视化免疫介导的休眠损伤的能力可能会发现潜在的 生物标志物，可能可翻译用于高危人类患者的早期检测，例如 免疫抑制的器官移植接受者患皮肤癌的风险增加100倍。