In situ anti-tumor immunity and effects of radiation

描述（由申请人提供）：本研究的目的是确定放射治疗如何改变实体瘤的各种成分，这些成分可能影响免疫系统产生有效抗肿瘤反应的能力。这些研究的目的是更好地了解辐射诱导肿瘤微环境变化的基本机制，以实现更有效的放射和免疫治疗相结合的治疗策略。这两种治疗方式的差异使得它们的联合使用很可能对肿瘤破坏产生协同作用。放射治疗在杀死大量肿瘤细胞和控制原发性疾病方面非常有效，但是，它不容易用于治疗播散性转移性疾病。相比之下，免疫疗法由于其特异性和全身性质，具有对正常组织毒性较小并到达远处转移的潜力。然而，放射治疗本身可能会损害免疫系统的关键细胞，特别是在多辐射剂量方案中，其中后续治疗可能会破坏肿瘤浸润淋巴细胞。我们已经表明，辐射诱导的肿瘤细胞死亡可以提供增加的肿瘤抗原来刺激免疫，并且辐射可以改变肿瘤血管系统，使其更易于宿主细胞浸润。这些肿瘤浸润性宿主细胞产生许多细胞因子，这些细胞因子可以刺激肿瘤脉管系统和肿瘤基质的变化，从而改变生长潜力和辐射敏感性。例如，我们已经表明，局部肿瘤微环境中产生的白细胞介素-12（IL-12）通过阻止血管内皮生长因子（VEGF）受体3的上调导致增强的免疫细胞浸润和延迟的肿瘤生长或排斥而引起肿瘤脉管系统的显著变化。在这个提议中，我们计划确定负责这些IL-12诱导的肿瘤血管系统和免疫细胞浸润和功能的变化的机制，并确定干扰素-γ（IFN-g）在这些过程中的作用。由于IFN-g在这些IL-12诱导的变化和使肿瘤细胞更具放射抗性的改变中的重要性，我们还将确定IFN-g信号介导放射抗性的机制以及这些机制如何影响肿瘤的免疫敏感性。我们获得的信息将有助于改善放射治疗和免疫治疗的组合，以更有效地治疗癌症患者。

DESCRIPTION (provided by applicant): The purpose of this research is to determine how radiation therapy alters the various components of solid tumors that may affect the immune system's ability to mount effective anti-tumor responses. The goal of these studies is to gain a better understanding of the basic mechanisms involved in radiation induced changes in the tumor microenvironment to allow more effective treatment strategies combining radiation and immunotherapy. The differences in these two therapy modalities make it highly likely that their combined use could have synergistic effects on tumor destruction. Radiation is highly effective at killing large numbers of tumor cells and controlling primary disease, however, it is not easily used for the treatment of dissem- inated metastatic disease. In contrast immunotherapy, because of its specificity and systemic nature, has the potential to be less toxic to normal tissues and to reach distant metastases. However, radiation therapy may itself be damaging to critical cells of the immune system, particularly in multi-radiation dose protocols in which subsequent treatments may destroy tumor infiltrating lymphocytes. We have shown that radiation induced tumor cell death can provide increased tumor antigen to stimulate immunity, and radiation can alter the tumor vasculature making it more prone to host cell infiltration. These tumor infiltrating host cells produce many cytokines, which can stimulate changes in the tumor vasculature and tumor stroma and thus alter growth potential and radiation sensitivity. For example, we have shown that interleukin-12 (IL-12), produced within the local tumor microenvironment, causes marked changes in the tumor vasculature by preventing the upregulation of vascular endothelial growth factor (VEGF) receptor 3 leading to enhanced immune cell infiltration and delayed tumor growth or rejection. In this proposal we plan to determine the mechanisms responsible for these IL-12 induced changes in tumor vasculature and in the immune cell infiltration and function, and determine the role of interferon-gamma (IFN-g) in these processes. Due to the importance of IFN-g in these IL-12 induced changes and in alterations that render tumor cells more radioresistant, we will also determine the mechanisms by which IFN-g signally mediates radioresistance and how these affect immune sensitivity of tumors. The information we obtain will be useful in improving the combination of radiotherapy and immunotherapy to more effectively treat patients with cancer.