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免疫治疗。 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癌症的模型，因此仍然存在一个被忽视的问题 在免疫逃避特性发展之前靶向肿瘤的机会。缺乏模型， 体内从头追踪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，一种新的小鼠模型已经被开发出来。 开发的，它允许在皮肤中的单个转化克隆的荧光示踪。一种特殊的移植 技术已被用于将荧光、转化诱导型角质形成细胞整合到表皮中， 免疫活性小鼠，在那里他们产生分离的，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侵入性成像。这 这项技术首次提供了原位癌症发展的直接可视化。既然豁免权代表着 肿瘤成功生长的关键障碍，该模型被设计为允许可视化 免疫细胞也是。免疫编辑的概念为癌症如何进化免疫提供了一个框架。 在发展过程中的策略。免疫编辑包括一种延长的休眠，称为免疫编辑。 “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，并揭示了正常组织微环境在早期 免疫逃避这种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阶段。在平衡阶段， 转化的细胞可能对干预特别敏感，因为它们的较低数量和相对较低的细胞毒性。 同质性将阻碍抗性机制的发展。重新想象的能力 在这个模型中的转换允许这个假设进行测试。此外，该模型将允许 表征介导免疫编辑的隐藏事件的机制。新的初步数据显示， 从平衡损伤到逃逸肿瘤的转变涉及逃逸过程中TGFβ3的上调， 肿瘤，其同时经历上皮-间充质转化。TGFβ3转化水平的增加 能够抑制肿瘤生长的NK细胞转化为不能抑制肿瘤生长的中间1型先天淋巴细胞 增长这一修订后的申请将进一步追求细胞和分子机制建议， 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 生物标志物，这可能是翻译为早期检测高风险的人类患者，如 免疫抑制的器官移植接受者，他们患皮肤癌的风险增加了100倍。