Synergy of Radiation and Immunotherapy: New Approaches

描述（由申请人提供）：分级局部放射治疗（RT）仍然是许多类型癌症的主要治疗方法。然而，对于许多大肿瘤，局部衰竭是常见的。成功操纵肿瘤微环境以改善放射治疗的策略正在深入研究中。虽然消融性放疗直接杀死肿瘤细胞，但我们意外地观察到，消融性放疗后的初始肿瘤控制在很大程度上依赖于I型IFN和T细胞，但辐照如何诱导IFN以及IFN如何帮助T细胞尚不清楚，RT诱导的损伤也可能触发组织修复级联反应，如诱导tgf β，其诱导m2样巨噬细胞，这与抑制RT启动免疫相关，可能导致肿瘤复发。通过对各种细胞因子和共刺激分子的初步筛选，我们发现与单一治疗相比，RT后局部递送IL-21可以改善微环境，控制肿瘤生长。我们假设，RT后抑制的M2巨噬细胞可以被重定向到M1巨噬细胞，以最大限度地提高抗肿瘤免疫。在目标1中，我们将定义消融RT如何积极和消极地调节免疫反应。一方面，我们将研究局部RT如何打破肿瘤屏障，诱导DNA-cGAS-STING进入I型IFN通路。另一方面，我们将研究rt介导的组织损伤如何逐渐诱导抑制性M2巨噬细胞导致肿瘤复发。在aim 2中，我们将研究RT后给药IL-21如何协同扩大T细胞反应并降低RT耐药性。我们将研究rt诱导的微环境变化如何允许IL-21-Fc靶向将抑制性M2重定向到支持性M1巨噬细胞，从而防止复发。我们将确定这种协同作用是否取决于巨噬细胞和/或树突状细胞的细胞因子增加以进行交叉启动。在目标3中，我们将生成Her2/ new依赖的散发性肿瘤。然后，我们研究RT是否以及如何在遗传诱导的自发性肿瘤模型或远端转移中与免疫治疗协同作用。因此，我们可以进一步评估局部RT是否可以增强ab - il21介导的针对散发性肿瘤模型和RT耐药或转移性肿瘤的免疫。了解放疗后肿瘤微环境的变化将有助于我们设计更好的联合策略来控制治疗诱导的耐药，并建立持久的保护。

DESCRIPTION (provided by applicant): Fractionated local radiation therapy (RT) remains a primary treatment for many types of cancer. However for many large tumors, local failure is common. Strategies to successfully manipulate the tumor microenvironment to improve radiotherapy are under intensive investigation. Although ablative RT kill tumor cells directly we unexpectedly observed that initial tumor control following ablative RT is largely dependent on type I IFN and T cells but how irradiation induces IFN and how IFN helps T cells are less clear, RT-induced damage might also trigger tissue repair cascades, such as induction of TGFbeta, which induces M2-like macrophages which are associated with dampened RT initiated immunity potentially leading to tumor relapse. After initial screening with various cytokines and co-stimulatory molecules we find that local delivery of IL-21 after RT can improve microenvironment and controls tumor growth compared with either single treatment. We hypothesize that suppressive M2 macrophages post RT can be redirected to M1 macrophages to maximize anti-tumor immunity. In aim 1, we will define how ablative RT both positively and negatively regulates immune responses. On one hand, we will study how local RT breaks tumor barriers and induces DNA-cGAS-STING for type I IFN pathway. On the other hand, we will study how RT-mediated tissue damage gradually induces suppressive M2 macrophages for tumor relapse. In aim 2, we will study how IL-21 administration after RT can synergistically expand T cell responses and reduce RT resistance. We will study how RT-induced changes in microenvironment permits IL-21-Fc targeting to redirect suppressive M2 to supportive M1 macrophages that prevent relapse. We will determine whether such synergy depends on increased cytokines for macrophages and/or dendritic cells for cross-priming. In aim 3, we will generate a Her2/neu-dependent sporadic tumor. We then study whether and how RT can synergize with immunotherapy in genetically induced spontaneous tumor model or distal metastasis. We can thus further evaluate whether local RT can enhance Ab-IL21-mediated immunity against sporadic tumor model and RT-resistant or metastatic tumor. Understanding of changing tumor microenvironment after RT will help us design better combination strategies to control treatment-induced resistance and establish long- lasting protection.