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.

对癌症免疫抗性的了解最近导致了革命性的免疫疗法和 随后，行业和学术界都急于确定免疫抑制的其他机制 由癌细胞雇用。由于这些努力依赖于成熟癌症的模型，因此仍然被忽略 在发展免疫反射特征之前，有机会靶向肿瘤。缺乏模型 在体内从头躯体转化的迹象阻止了早期癌变的直接表征 包括与免疫细胞的首次相互作用。为了解决这一缺陷，新颖的鼠标模型已经 开发，可以荧光追踪皮肤中的单个转化克隆。特殊的移植 技术已用于将荧光，转化诱导的角质形成细胞整合到表皮中 一种免疫能力的小鼠，它们产生了孤立的稳态克隆。这些菌落可能不是 随着转化的诱导，通过插入式共聚焦显微镜在亚细胞分辨率上成像。这 技术提供了原位癌症发展的首个直接可视化。由于免疫力代表 肿瘤成功生长的关键障碍，该模型经过设计，以允许可视化 免疫细胞。免疫编辑的概念为癌症如何进化免疫提供了一个框架 - 发展过程中的回避策略。免疫程序包括长时间的休眠，称为 “平衡阶段”，在此期间免疫可防止肿瘤的生长，而不会破坏转化的细胞。 该模型首次允许观察所有三个阶段的免疫修订：消除，， 平衡和逃脱，并揭示了正常组织微环境在早期起着核心作用 免疫进化。这个新颖的模型还揭示了免疫初期的先天免疫细胞的作用 对皮肤癌的监测和平衡阶段的维持。在平衡阶段， 转化的细胞可能对干预措施唯一敏感，因为它们的数量较低和相对 同质性将妨碍发展抵抗机制。从头可视化的能力 该模型中的转换允许检验该假设。此外，该模型将允许 介导免疫编辑的隐藏事件的机制的表征。揭示了新的初步数据 从平衡病变逃脱肿瘤的过渡涉及TGFβ3在逃生中的上调 肿瘤，同时经历上皮 - 间质转变。 TGFβ3的水平增加了 可以抑制肿瘤生长的NK细胞进入中间1型先天淋巴样细胞，无法抑制肿瘤 生长。修订后的应用将进一步追求由细胞和分子机制提出的 这些初步数据。最后，可视化免疫介导的休眠病变的能力可能会发现潜力 生物标志物，在高危人类患者中可能是可转换的，例如 免疫抑制的器官移植受者，患有皮肤癌的风险增加了100倍。