Generation and analysis of immunity inside tumor tissues

描述(申请人提供)：Yu博士的长期目标是了解免疫系统如何对同基因癌细胞和组织做出反应，以及如何促进更强大的免疫反应来对抗恶性肿瘤。目前的应用旨在揭示新发现的肿瘤坏死因子超家族(TNFSF)成员LIGHT如何诱导强大的抗肿瘤免疫的机制，并在临床相关环境下测试LIGH在肿瘤免疫治疗中的应用。我们知道光可以诱导免疫介导的肿瘤排斥反应，然而，光如何激发如此强大的抗肿瘤免疫的机制还没有得到很好的研究。我们坚信LIGH是自发转移性疾病肿瘤免疫治疗的一个很好的候选药物，但其全部潜力尚未确定。我们的初步数据表明，光不仅可以吸引和刺激肿瘤特异性CD8+T细胞，而且还可以调节NK和CD4+调节性T细胞。此外，我们的初步研究表明，利用腺光载体确实可以治疗小鼠模型中的自发转移。我们认为，与许多其他共刺激分子不同，光具有通过其受体LT？调节基质和造血免疫途径的优势。受体(LT？R)和疱疹病毒进入介体(HVEM)。具体地说，这些目标将以以下三个具体目标为目标：目的1：研究光介导的肿瘤环境如何促进NK细胞在诱导肿瘤排斥反应中的功能，并确定NK细胞在抗肿瘤免疫中的作用。目的2：明确LIGH在调节肿瘤内的CD4+抑制T细胞中的作用。目的3：明确LIGH在自发转移肿瘤模型中促进免疫识别的作用。这项研究的预期结果将确定光介导抗肿瘤免疫的机制，并确定将具有临床意义的光传递到肿瘤组织的方式。这项研究还将阐明光是否可以用作治疗转移性疾病的潜在治疗剂。外行语言：尽管有证据表明肿瘤抗原可以被免疫系统识别，但癌症的自发消退很少发生。表达在肿瘤上的分子光可以诱导肿瘤快速消退。这项应用旨在探索涉及的机制，以及开发临床相关的癌症治疗用光。

DESCRIPTION (provided by applicant): Dr. Yu's long term goal is to understand how the immune system responds to syngeneic cancerous cells and tissues, and how stronger immune responses can be promoted against the malignancies. The current application is intended to uncover the mechanisms of how LIGHT, a newly-identified tumor necrosis factor superfamily (TNFSF) member, induces a strong anti-tumor immunity and test the application of LIGHT to tumor immunotherapy in a clinically relevant setting. We know that LIGHT can induce an immune-mediated tumor rejection, however, the mechanisms of how LIGHT provokes such a strong anti-tumor immunity has not been well studied. We strongly believe that LIGHT is a good candidate for tumor immunotherapy in spontaneous metastatic disease, but its full potential has yet to be determined. Our preliminary data suggests that LIGHT can not only attract and stimulate tumor-specific CD8+ T cells, but also regulate NK and CD4+ regulatory T cells. Moreover, our pilot study demonstrates that the utilization of an adeno-LIGHT vector can indeed treat spontaneous metastases in a mouse model. We propose that LIGHT, unlike many other co-stimulatory molecules, has the advantage to regulate both the stromal and hematopoietic immune pathways via its receptors, LT? receptor (LT?R) and Herpes Virus Entry Mediator (HVEM). Specifically, these goals will be pursued with the following three specific aims: Aim 1: To investigate how LIGHT-mediated tumor environment promotes NK function in eliciting tumor rejection and define the roles of NK cells in anti-tumor immunity. Aim 2: Define the role of LIGHT in regulation of CD4+ suppressive T cells inside the tumor. Aim 3: Define the role of LIGHT in promoting immune recognition in spontaneous metastatic tumor models. The expected results from this research will define the mechanisms by which LIGHT mediates anti-tumor immunity and determine ways of delivering LIGHT into the tumor tissue that would be clinically relevant. This study will also elucidate if LIGHT can be utilized as a potential therapeutic agent for treating metastatic disease. Lay language: Despite evidence of tumor antigens that can be recognized by immune system, spontaneous regression of cancers rarely occurs. A molecule LIGHT, expressed on tumors, can induce a rapid tumor regression. This application intends to explore the mechanisms involved as well as develop clinically relevant cancer therapy with LIGHT.