Genetic factors influencing the immune response to carcinomas in skin cancer

描述（由申请人提供）：免疫调节剂是一类新型靶向化疗剂，可调节免疫应答。这些药物已经显示出作为一线和辅助抗癌治疗的巨大前景。这些药物的作用机制被认为涉及调节免疫系统的活性状态，可能激活先前抑制的抗肿瘤反应。通过使用免疫系统治疗恶性肿瘤，肿瘤学家有可能在目前缺乏有效治疗方案的人群中产生持久的反应，例如恶性黑色素瘤患者。尽管他们取得了成功，但仍有严重的副作用和肿瘤反应的不一致性。因此，了解哪些遗传和免疫因素是肿瘤对免疫调节治疗产生反应的倾向的基础，对于最大限度地发挥这些药物的益处至关重要。为此，我计划在致癌物诱导的皮肤癌小鼠模型中表征免疫系统和肿瘤细胞之间的相互作用。在该模型中，小鼠产生两种不同类型的癌：依赖于长期炎症的A类癌;和不太依赖于长期炎症的B类癌。这些肿瘤类型表现出不同的突变和基因表达调节模式，以及与免疫系统的差异相互作用。通过研究导致这些肿瘤亚型发展和进展的遗传和免疫因素，以及在一项新的模拟临床试验中测试免疫调节剂ipilimumab的疗效，我们希望证明可以通过表征定义肿瘤的遗传病变和浸润细胞群来识别易感肿瘤亚型。这些调查的结果 将是对影响肿瘤易感性的免疫系统遗传因素的更深入理解，以及对可能对免疫调节治疗无反应的遗传学定义的肿瘤类型的初步表征。

DESCRIPTION (provided by applicant): Immunomodulatory agents are a novel class of targeted chemotherapeutic agents that modulate the immune response. These agents have shown tremendous promise as frontline and adjuvant anticancer therapeutics. The mechanism of action of these agents is thought to involve tuning the activity state of the immune system, potentially activating a previously suppressed anti-tumor response. By using the immune system to treat malignancies, oncologists have the potential to effect durable responses in populations which currently lack effective treatment options, such as those with malignant melanoma. Despite their successes, serious side effects and inconsistencies in tumor response have been reported. Understanding what genetic and immunological factors underlie the propensity of a tumor to respond to immunomodulatory therapy is therefore of pivotal importance in order to maximize the benefits of these agents. To this end I plan on characterizing the interactions between the immune system and tumor cells in a mouse model of carcinogen induced skin cancer. In this model mice develop two distinct classes of caricnomas: class A carcinomas dependent upon prolonged inflammation; and class B carcinomas which are less dependent upon prolonged inflammation. These tumor types demonstrate distinct patterns of mutation and gene expression modulation, as well as differential interactions with the immune system. By studying the genetic and immunological factors contributing to the development and progression of these tumor subtypes, as well as testing the efficacy of the immunomodulatory ipilimumab in a novel mock clinical trial, we hope to demonstrate that susceptible tumor subtypes can be identified by characterizing the genetic lesions and infiltrating cell populations which define a tumor. The product of these investigations will be a deeper understanding of genetic elements of the immune system influencing tumor susceptibility, as well as preliminary characterization of genetically defined tumor types likely t respond to immunomodulatory therapy.