Synergy of radiation and immunotherapy: new approaches

描述（由申请人提供）：我们的主要目标是开发新的策略，以大大降低原发性肿瘤负荷，同时增强免疫力，以根除局部和远端转移。已建立的肿瘤形成限制免疫破坏的物理/免疫屏障。我们最近的研究结果表明，大剂量单次RT特异性靶向原发性肿瘤的治疗效果可以通过增加CTL交叉致敏和显着增加抗原呈递来打破这些肿瘤屏障，从而导致对已建立肿瘤的排斥。局部RT诱导的CTL交叉引发可以通过表达LIGHT（Ad-LIGHT）、TNF超家族-14的腺病毒的局部肿瘤递送来进一步扩增，其增加肿瘤浸润DC（TIDC）和T细胞（TIL），导致转移的清除。此外，针对转移的免疫保护可以被标准化疗消除。现在，我们的初步数据表明，这种RT诱导的肿瘤消退也依赖于I型IFN和β-光敏素受体（LT R），一种LIGHT和β-光敏素（LT）的受体。我们假设，局部RT诱导内源性危险信号和LT？R信号，共同刺激肿瘤内I型IFN的产生，以募集和功能成熟的DC，有效地引发CTL和增强抑制性肿瘤微环境。在目标1中，我们将研究RT如何控制CTL。我们将确定RT是否以I型IFN依赖性方式增加引流淋巴结中CTL的引发，以及配备有交叉引发能力的TIDCs是否对肿瘤微环境内CTL效应子功能的保留至关重要。在目标2中，我们将确定I型IFN信号传导是否以及如何控制TIDC。我们将测试I型IFN信号传导是否增加TIDCs的数量和功能。我们还将研究是否以及如何提供外源性干扰素可以重演的影响，当地RT的TIDC功能。在目标3中，我们将确定哪些细胞产生I型干扰素后RT。我们将研究如何RT介导的危险信号控制I型干扰素的生产和TIDC功能。在目标4中，我们将研究LT R信号传导对TIDC和I型IFN产生的作用，以用于RT介导的肿瘤减少。我们将测试I型IFN和LTb受体途径如何协调以产生功能性TIDCs并介导RT诱导的肿瘤生长控制。我们将确定局部RT和ad-LIGHT免疫疗法如何通过内源性危险信号和I型IFN产生协同连接先天性和适应性免疫。因此，我们的研究将揭示RT诱导的肿瘤消退的新机制，并有助于开发新的策略来启动先天性和适应性免疫的级联反应。 公共卫生相关性：肿瘤形成物理屏障和免疫抑制环境。我们的研究表明，局部放射不仅可以减少肿瘤负荷，还可以刺激有意义的免疫力。因此，重要的是研究其诱导免疫的机制，这使我们能够更好地开发一种新的，临床相关的和高效的联合治疗模式，用于癌症的各个阶段，包括转移。

DESCRIPTION (provided by applicant): Our major goal is to develop new strategies to greatly reduce primary tumor burden while boosting immunity for the eradication of local and distal metastases. Established tumors form physical/immunological barriers that limit immune destruction. Our recent findings show that the therapeutic effect of large single dose RT targeted specifically to the primary tumor can break these tumor barriers by increasing CTL cross-priming and dramatically increasing antigen presentation, which lead to rejection of established tumors. The local RT-induced cross-priming of CTL can be further amplified by local tumor delivery of an adenovirus expressing LIGHT (Ad-LIGHT), TNF superfamily-14, which increases tumor infiltrating DCs (TIDCs) and T-cells (TIL) resulting in the clearance of metastases. Furthermore, the immune protection from metastasis can be erased by standard chemotherapy. Now our preliminary data indicate that such RT-induced tumor regression also depends on type I IFN and lymphotoxin beta receptor (LT¿R), a receptor for LIGHT and lymphotoxin (LT). We hypothesize that local RT induces endogenous danger signals and LT¿R signaling that together stimulate type I IFN production inside the tumor to recruit and functionally mature DCs for efficient priming of CTL and augmentation of the suppressive tumor microenvironment. In aim 1, we will investigate how RT controls CTLs. We will determine whether RT increases the priming of CTLs in the draining lymph node in a type I IFN dependent fashion and whether TIDCs equipped with cross-priming capacity are essential for the preservation of CTL effector function within the tumor microenvironment. In aim 2, we will determine whether and how type I IFN signaling controls TIDC. We will test whether type I IFN signaling augments the number and function of TIDCs. We will also study whether and how provision of exogenous IFN can recapitulate the effects of local RT on TIDC function. In aim 3, we will identify which cells produce type I IFN following RT. We will study how RT-mediated danger signals control type I IFN production and TIDC function. In aim 4, we will study the role of LT¿R signaling on TIDCs and type I IFN production for RT-mediated tumor reduction. We will test how type I IFN and LTb receptor pathways coordinate to generate functional TIDCs and mediate RT-induced tumor growth control. We will determine how local RT and immunotherapy with ad-LIGHT can synergistically link innate and adaptive immunity through endogenous danger signals and type I IFN production. Therefore, our study will reveal new mechanisms for RT-induced tumor regression and aid in the development of new strategies to initiate a cascade of innate and adaptive immunity. PUBLIC HEALTH RELEVANCE: Tumors form physical barriers and immunosuppressive environments. Our study has now shown that local radiation not only reduces tumor burden but also stimulates meaningful immunity. Therefore, it is important to study its mechanisms for induction of immunity which allow us to better develop a novel, clinically relevant and highly effective combination treatment modality for various phases of cancer, including metastases.