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，以大大减少原发肿瘤负担，同时提高免疫力，根除局部和远端转移。已形成的肿瘤形成物理/免疫屏障，限制免疫破坏。我们最近的研究结果表明，针对原发肿瘤的大剂量RT的治疗效果可以通过增加CTL交叉引物和显著增加抗原呈递来打破这些肿瘤屏障，从而导致已建立肿瘤的排斥反应。通过肿瘤局部递送表达LIGHT （Ad-LIGHT）、TNF超家族-14的腺病毒，可进一步扩增局部rt诱导的CTL交叉启动，从而增加肿瘤浸润性dc （TIDCs）和t细胞（TIL），从而清除转移灶。此外，免疫保护转移可以消除标准化疗。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和淋巴素β受体（LT¿R），一种LIGHT和淋巴素（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，招募和功能成熟的dc，以有效启动CTL和增强抑制肿瘤微环境。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依赖的方式增加引流淋巴结中CTL的启动，以及具有交叉启动能力的tidc是否对肿瘤微环境中CTL效应功能的保存至关重要。在目标2中，我们将确定I型IFN信号是否以及如何控制TIDC。我们将测试I型IFN信号是否会增加tidc的数量和功能。我们还将研究外源性IFN的提供是否以及如何概括局部RT对TIDC功能的影响。在目标3中，我们将确定哪些细胞在rt后产生I型IFN。我们将研究rt介导的危险信号如何控制I型IFN的产生和TIDC功能。在目标4中，我们将研究LT¿R信号在tidc和I型IFN产生中对rt介导的肿瘤减少的作用。我们将测试I型IFN和LTb受体通路如何协调产生功能性tidc并介导rt诱导的肿瘤生长控制。我们将确定局部RT和ad-LIGHT免疫治疗如何通过内源性危险信号和I型IFN产生协同连接先天免疫和适应性免疫。因此，我们的研究将揭示rt诱导肿瘤消退的新机制，并有助于开发启动先天和适应性免疫级联反应的新策略。

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.