Host-tumor interactions and cancer relapse after radiation therapy

项目摘要 尽管放射治疗(放射治疗，例如，图像引导和强度调制放射治疗)的进步导致 为了改善治疗结果，克服肿瘤复发仍然是一些 RT是一种重要的治疗手段的癌症。越来越多的人意识到 恶性肿瘤细胞与未转化的宿主细胞(如免疫细胞、内皮细胞)之间的相互作用 细胞)不仅决定癌症行为(例如，侵袭和转移)，而且还决定对治疗的反应， 包括RT。然而，肿瘤内分子和细胞相互作用的确切机制 微环境(TME)及其对放疗后复发的影响仍有待阐明。中心假说 在基于我们的初步数据制定的本申请中，清道夫受体A(SRA)是一种模式 识别分子主要表达在髓系细胞上，通过促进 促血管生成、肿瘤相关巨噬细胞(TAMs)极化与肿瘤血管重建 RT.我们的总体目标是全面了解SRA作为 控制动态髓系细胞-肿瘤串扰和肿瘤放射治疗反应的基本宿主因素。这个 拟议研究的基本原理是，描绘SRA在调节中的基本机制 TME对RT的反应具有开发新的靶向方法来降低癌症的潜力 在临床上复发。我们将通过追求3个具体目标来检验我们的假设：1)为 SRA在促进放疗后肿瘤血管恢复和随后复发中的作用 生化和细胞方法与临床相关的模型系统；2)确定分子和 SRA功能的细胞基础使肿瘤相关巨噬细胞偏向交替激活的， 前血管生成表型；以及3)验证靶向SRA在TME中的概念以克服RT后 通过参与多价抗肿瘤机制而复发。鉴于已建立的免疫抑制机制 除了SRA的功能外，我们还将评估在TME中阻止SRA活动的可行性，以改善 基于RT和热休克蛋白的联合治疗的有效性。 相关SRA作为治疗结果的关键、肿瘤外在决定因素的概念 在RT之后，通过拮抗TME中的SRA来消灭肿瘤以防止癌症复发的想法 血运重建和同时增强免疫功能是创新的。拟议的研究是 意义重大，因为它有望促进对动态宿主-肿瘤的不同方面的理解 相互作用及其在改善肿瘤放疗反应中的意义。从这些研究中获得的见解 有助于合理设计多种治疗方法，减少放疗后治疗失败。

Project Summary Although advances in radiation therapy (RT, e.g., image-guided and intensity-modulated RT) have led to improved treatment outcomes, overcoming tumor recurrence still remains a challenge for a number of cancers where RT is an important therapeutic modality. There is an increasing appreciation of how dynamic interactions between malignant tumor cells and non-transformed host cells (e.g., immune cells, endothelial cells) determine not only cancer behavior (e.g., invasion and metastasis), but also responses to therapies, including RT. However, the precise mechanisms of molecular and cellular interactions within the tumor microenvironment (TME), and their impact on post-RT relapse remain to be elucidated. The central hypothesis in this application, formulated based on our preliminary data, is that scavenger receptor A (SRA), a pattern recognition molecule primarily expressed on myeloid cells, promotes tumor recurrence by facilitating the polarization of proangiogenic, tumor-associated macrophages (TAMs) and tumor revascularization following RT. Our overall objective is to comprehensively understand a previously unrecognized role of SRA as an essential host factor in governing dynamic myeloid cell-tumor crosstalk and tumor response to RT. The rationale for the proposed research is that delineating fundamental mechanisms of SRA action in modulating the TME in response to RT has the potential for developing novel targeted approaches to reduce cancer recurrence in the clinic. We will test our hypothesis by pursuing 3 specific aims: 1) Establish a crucial role for SRA in potentiating the recovery of tumor vasculature after RT and subsequent recurrence using genetic, biochemical, and cellular approaches with clinically relevant model systems; 2) Determine the molecular and cellular basis of SRA functions in skewing tumor-associated macrophages toward an alternatively activated, proangiogenic phenotype; and 3) Validate the concept of targeting SRA in the TME to overcome post-RT recurrence by engaging multivalent antitumor mechanisms. In view of the established immunosuppressive functions of SRA, we will also evaluate the feasibility of blocking SRA activity in the TME to improve the effectiveness of a combinatorial RT and heat shock protein-based therapy. The concept of TAM-associated SRA as a critical, tumor-extrinsic determinant of treatment outcome following RT, and the idea of preventing cancer relapse by antagonizing SRA in the TME to abrogate tumor revascularization and concurrently enhance immune functions are innovative. The proposed research is significant because it is expected to advance the understanding of distinct aspects of dynamic host-tumor interactions and their implications in improving tumor response to RT. The insights gained from these studies will facilitate rational design of multimodality therapy to reduce treatment failure after RT.