The B7x pathway in the tumor microenvironment

描述(申请人提供)：癌症免疫治疗的关键问题之一是确定肿瘤生长不同阶段的主要逃逸机制，并设计出克服这些机制的方法。我们已经确定B7x是T细胞共刺激和共抑制的B7家族中一个特征不佳的成员。我们的临床数据显示，B7x的异常表达在各种人类癌症中都可以观察到，并且经常与不良的临床结果有关。该项目的假设是，B7x是肿瘤微环境中的关键免疫逃避途径，阻断这一途径可产生治疗性肿瘤免疫。在我们已发表的癌症患者临床研究和我们强大的小鼠肿瘤模型初步数据的指导下，这一假说将通过三个具体目标进行验证：1)阐明肿瘤表达的B7x在疾病进展中的功能后果；2)确定宿主细胞表达的B7x在肿瘤进展中的作用机制；以及3)通过靶向B7x途径产生治疗性肿瘤免疫。我们创造了许多新颖的工具，并组建了一支拥有互补技能的多学科团队，这为我们提供了应对挑战和实现目标的独特机会。本研究的结果将为B7x通路在肿瘤微环境中的免疫逃逸机制提供新的见解，并为未来临床设计新的免疫疗法提供基础。

DESCRIPTION (provided by applicant): One of the key issues in cancer immunotherapy is to identify the dominant escape mechanisms during different phases of tumor growth and to devise ways to overcome them. We have identified B7x as a poorly characterized member of the B7 family of T cell costimulation and coinhibition. Our clinical data have revealed that aberrant expression of B7x is observed in a variety of human cancers and is often associated with poor clinical outcome. The hypothesis of this project is that B7x is a critical immune evasion pathway within the tumor microenvironment and blockade of this pathway generates therapeutic tumor immunity. Guided by our published clinical research with cancer patients and our strong preliminary data with murine tumor models, this hypothesis will be tested by pursuing three specific aims: 1) Elucidation of the functional consequence of tumor-expressed B7x in disease progression; 2) Determination of mechanistic contribution of host cell-expressed B7x to tumor progression; and 3) Generation of therapeutic tumor immunity by targeting the B7x pathway. We have generated a number of novel tools and have assembled a multi-disciplinary team with complementary skill sets, which provides us with unique opportunities to address challenges and realize goals. The outcomes of this research will provide novel insights into immune evasion mechanisms of the B7x pathway in the tumor microenvironment and provide the basis for future clinical design of a new immunotherapy.