Modular Model for Studies of Immunosurveillance in Skin Cancer

描述(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，包括角质形成细胞起源的皮肤癌，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。与非免疫抑制患者相比，医学免疫抑制患者，如器官移植受者，患SCC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强大的肿瘤促进作用。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。有证据表明，免疫反应可以加重和抑制肿瘤生长，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。这样的理解有可能指导直接使用免疫系统来摧毁肿瘤，也有可能区分免疫抑制药物和促进肿瘤药物的有益效果。我们的长期目标是在免疫系统靶向操作的基础上开发新的、有效的癌症治疗策略。这项应用的目的是验证一种可移植的小鼠鳞状细胞癌模型，该模型允许对肿瘤、药物诱导的免疫抑制和宿主免疫系统进行独立操作。我们的中心假设是，药物诱导的免疫抑制会通过改变渗透到肿瘤中的T细胞亚群的平衡来增加种植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，通过该框架可以为癌症治疗量身定做免疫调节剂。我们的研究团队包括癌症小鼠模型、抗原提呈细胞(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的SCC模型与外源性免疫抑制相结合，创建并验证用于免疫抑制小鼠肿瘤免疫学研究的临床相关的小鼠SCC模型；(2)实时识别免疫细胞亚群，特别是T调节细胞，对体内肿瘤种植和生长的贡献。 公共卫生相关性：免疫系统在控制皮肤癌，特别是鳞状细胞癌方面的关键重要性已在人类患者、相关的紫外线诱导和药物诱导的免疫抑制以及炎症和癌症的新出现且往往相互冲突的角色中得到令人信服的证明。迫切需要更好地了解肿瘤-宿主-免疫系统的相互作用，以便进一步促进免疫系统在癌症治疗中的直接使用。我们的目标是在免疫能力强的小鼠中开发一种模块化的免疫监控模型，该模型将能够独立操作肿瘤细胞和宿主免疫系统，从而更容易开发出机械洞察力和治疗干预措施。

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.