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带来了革命性的免疫疗法和 随后，工业界和学术界都急于确定免疫抑制的其他机制 被癌细胞利用。由于这些努力依赖于成熟的癌症模型，因此仍然存在一个被忽视的问题 在免疫逃避特征发展之前有机会靶向肿瘤。缺乏模型 追踪体内从头体细胞转化阻止了早期癌发生的直接表征， 包括与免疫细胞的第一次相互作用。为了解决这一缺陷，研究人员开发了一种新型小鼠模型 开发出来的技术可以对皮肤中的单个转化克隆进行荧光追踪。特殊移植 技术已被用来将荧光、转化诱导的角质形成细胞整合到表皮中 具有免疫功能的小鼠，它们在其中产生分离的稳态克隆。这些菌落可以是非 当诱导转化时，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 该技术首次提供了癌症原位发展的直接可视化。由于免疫力代表 肿瘤成功生长的关键障碍，该模型经过精心设计，可实现可视化 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 其发展过程中的回避策略。免疫编辑包括长期休眠，称为 “平衡期”，在此期间免疫防止肿瘤生长而不破坏转化的细胞。 该模型首次允许观察免疫编辑的所有三个阶段：消除、 平衡和逃逸，揭示了正常组织微环境在早期 免疫逃避。这种新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阶段。在平衡阶段， 转化细胞可能对干预措施特别敏感，因为它们的数量较少且相对 同质性将阻碍耐药机制的发展。从头可视化的能力 该模型中的变换允许检验该假设。此外，该模型将允许 介导免疫编辑隐藏事件的机制的表征。新的初步数据揭晓 从平衡病变到逃逸肿瘤的转变涉及逃逸中TGFβ3的上调 肿瘤，同时经历上皮间质转化。 TGFβ3 转化水平增加 可以抑制肿瘤生长的NK细胞，转化为不能抑制肿瘤的中间1型先天淋巴细胞 生长。该修订后的申请将进一步追求由 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揭示潜在的潜力 生物标志物，可用于高危人类患者的早期检测，例如 免疫抑制的器官移植受者，患皮肤癌的风险增加 100 倍。