Modular Model for Studies of Immunosurveillance in Skin Cancer

描述（由申请人提供）：皮肤癌是人类最常见的恶性肿瘤。在美国，每年有超过150万例皮肤癌，包括角化细胞起源的皮肤癌，如基底细胞癌和鳞状细胞癌，以及黑色素瘤。众所周知，皮肤癌，尤其是鳞状细胞癌（SCC）的行为明显受到患者免疫状态的影响。医源性免疫抑制患者，如器官移植受者，发生SCC的风险是非免疫抑制个体的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强大的促肿瘤作用。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。鉴于有证据表明免疫反应可以加剧和抑制肿瘤的生长，因此迫切需要研究免疫系统在皮肤癌的发生、发展和治疗中的作用。这样的理解有可能为直接使用免疫系统来破坏肿瘤提供信息，也有可能将免疫抑制药物的有益作用与促进肿瘤的药物区分开来。我们的长期目标是开发基于免疫系统靶向操作的新型有效的癌症治疗策略。本应用程序的目的是验证小鼠可移植鳞状细胞癌模型，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会通过改变浸润肿瘤的t细胞亚群的平衡来增加植入的鳞状细胞癌的侵袭性。这些研究的基本原理是确定免疫系统-肿瘤相互作用的关键介质将牢固地建立一个框架，通过该框架，免疫调节剂可能适合癌症治疗。我们的研究团队包括癌症小鼠模型、抗原呈递细胞(APC) - t细胞相互作用以及皮肤癌免疫抑制方面的专家。我们的目标是(1)通过将免疫原性可移植SCC模型与外源性免疫抑制相结合，在免疫抑制小鼠中建立并验证临床相关的SCC小鼠模型，用于癌症免疫学研究；(2)实时识别免疫细胞亚群，特别是T调节细胞，对体内肿瘤植入和生长的贡献。

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.