Modular Model for Studies of Immunosurveillance in Skin Cancer

皮肤癌免疫监视研究的模块化模型

• 批准号: 7879729
• 负责人: Kenneth Y Tsai
• 金额: $ 7.9万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7879729
• 关键词: Affect; Antigen-Presenting Cells; B-Lymphocytes; Basal Cell; Behavior; Biological Models; Cancer Immunology Science; Cell Communication; Cells; Chronic; Conflict (Psychology); Containment; Cyclosporine; Cyclosporins; Data; Development; Equilibrium; Funding; Goals; Grant; Growth; Human; Human Papillomavirus; Immune; Immune response; Immune system; Immunocompetent; Immunocompromised Host; Immunologic Monitoring; Immunosuppression; Implant; Individual; Infection; Inflammation; Injury; Knock-out; Lead; Malignant Neoplasms; Mediator of activation protein; Modeling; Molecular; Mus; Organ Transplantation; Patients; Pharmaceutical Preparations; Phase; Play; Population; Regulatory T-Lymphocyte; Relative (related person); Research; Role; Site; Skin Cancer; Squamous cell carcinoma; Study models; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Therapeutic Intervention; Time; Transgenic Mice; Transplant Recipients; Tumor Immunity; Ultraviolet Rays; United States; Viral Oncogene; base; cancer therapy; chemical carcinogen; clinically relevant; genetic manipulation; high risk; immunogenic; immunosuppressed; implantation; in vivo; innovation; insight; intradermal injection; melanoma; mouse model; neoplastic cell; novel; public health relevance; therapy development; tumor; tumor growth

DESCRIPTION (provided by applicant): Skin cancer is the most common class of malignancy in humans. In the United States, there are over 1.5 million cases of skin cancer a year, including those of keratinocytic origin such as basal cell and squamous cell carcinoma, and melanoma. It is well known that the behavior of skin cancer, most notably squamous cell carcinoma (SCC), is markedly affected by the immune status of patients. Iatrogenically immunosuppressed patients, such as organ transplant recipients, have a 65-250-fold higher risk of SCC relative to non- immunosuppressed individuals. Evidence from multiple human cancers demonstrates that inflammation from chronic injury or infection has potent tumor-promoting effects. Evidence from model systems indicates that some subpopulations of T-cells and B-cells have differing effects on tumor growth. Given the evidence that immune responses can aggravate and inhibit tumor growth, there is a critical need to investigate the roles of the immune system in the initiation, development, and treatment of skin cancer. Such an understanding has the potential to inform directed use of the immune system to destroy tumors and also has the potential to separate the beneficial effects of immunosuppressive medications from tumor-promoting ones. Our long-term goal is to develop novel and effective therapeutic strategies for cancer based upon targeted manipulation of the immune system. The objective of this application is to validate a transplantable squamous cell carcinoma model in mouse that permits independent manipulation of the tumor, drug-induced immunosuppression, and the host immune system. Our central hypothesis is that drug-induced immunosuppression will increase the aggressiveness of implanted squamous cell carcinoma by altering the balance of T-cell subsets that infiltrate the tumor. The rationale for these studies is that the identification of key mediators of immune-system - tumor interactions will firmly establish a framework through which immune modulators may be tailored for cancer therapy. Our research team includes experts in mouse models of cancer, antigen presenting cell (APC) - T-cell interactions, as well as immunosuppression in skin cancer. We aim to (1) create and validate a clinically-relevant mouse model of SCC for studies of cancer immunology in immunosuppressed mice by combining an immunogenic transplantable SCC model with exogenous immunosuppression and (2) identify in real-time, the contribution of immune cell subsets, in particular T- regulatory cells, to tumor implantation and growth in vivo. PUBLIC HEALTH RELEVANCE: The critical importance of the immune system in controlling skin cancer, particularly squamous cell carcinomas, has been convincingly demonstrated in the context of human patients, associated ultraviolet light-induced and drug-induced immunosuppression, and in the emerging and often conflicting roles of inflammation and cancer. There is an urgent need to better understand tumor - host-immune system interactions so directed use of the immune system for cancer therapy can be further advanced. We aim to develop a modular model of immunosurveillance in immunocompetent mice that will enable the independent manipulation of tumor cells and the host immune system so that mechanistic insights and therapeutic interventions may be more readily developed.

描述（由申请人提供）：皮肤癌是人类最常见的恶性肿瘤类别。在美国，每年有超过150万例皮肤癌病例，其中包括角质形成原状，例如基底细胞和鳞状细胞癌和黑色素瘤。众所周知，皮肤癌的行为，最著名的是鳞状细胞癌（SCC），受到患者免疫状态的显着影响。与非免疫抑制个体相对于非免疫抑制的个体，诸如器官移植受者之类的多个免疫抑制患者（例如器官移植受者）的风险高65-250倍。来自多种人类癌症的证据表明，慢性损伤或感染引起的炎症具有​​有效的肿瘤促进作用。来自模型系统的证据表明，T细胞和B细胞的某些亚群对肿瘤生长有不同的影响。鉴于证据表明免疫反应会加剧和抑制肿瘤的生长，因此至关重要的是研究免疫系统在皮肤癌的启动，发育和治疗中的作用。这种理解有可能告知免疫系统破坏肿瘤的可能性，并有可能将免疫抑制药物的有益作用与促肿瘤促进药物区分开。我们的长期目标是基于对免疫系统的有针对性操纵来制定新颖有效的癌症治疗策略。该应用的目的是验证小鼠中可移植的鳞状细胞癌模型，该模型允许独立操纵肿瘤，药物诱导的免疫抑制和宿主免疫系统。我们的中心假设是，药物诱导的免疫抑制将通过改变浸润肿瘤的T细胞亚群的平衡来提高植入的鳞状细胞癌的侵略性。这些研究的理由是，鉴定免疫系统的关键介体 - 肿瘤相互作用将牢固建立一个框架，可以通过该框架为癌症治疗量身定制免疫调节剂。我们的研究团队包括癌症小鼠模型，抗原呈递细胞（APC）的专家 - T细胞相互作用以及皮肤癌中的免疫抑制。我们的目的是（1）通过将免疫原性的可移植SCC模型与外源性免疫抑制和（2）实时确定，在免疫细胞亚群中鉴定出免疫细胞亚基的贡献，特别是T型调节性细胞的贡献，在Tumor to tumor Plancation和Tumor Plancation in viv viV中，我们的目标是（1）通过将免疫原性的SCC模型与外源性免疫抑制和（2）实时确定的，并验证免疫抑制小鼠的癌症免疫学研究和验证。 公共卫生相关性：免疫系统在控制皮肤癌（尤其是鳞状细胞癌）中的至关重要性在人类患者的背景下令人信服地证明，相关的紫外线诱导和药物诱导的免疫抑制，以及在炎症和炎症和癌症的新兴和经常相互矛盾的作用中。迫切需要更好地了解肿瘤 - 宿主免疫系统的相互作用，因此可以进一步采用免疫系统用于癌症治疗的方法。我们旨在在免疫能力小鼠中开发一种模块化模型，该模型将使肿瘤细胞和宿主免疫系统独立操纵，以便更容易地开发机械洞察力和治疗性干预措施。