Host-tumor interactions and cancer relapse after radiation therapy

描述（由申请人提供）：尽管放射治疗（RT，例如，图像引导的和强度调节的RT）已经导致改善的治疗结果，但是克服肿瘤复发对于RT是重要治疗方式的许多癌症仍然是一个挑战。越来越多的人认识到恶性肿瘤细胞和非转化宿主细胞（例如，免疫细胞，内皮细胞）不仅决定癌症行为（例如，然而，肿瘤微环境（TME）内分子和细胞相互作用的确切机制及其对RT后复发的影响仍有待阐明。基于我们的初步数据，本申请的中心假设是清道夫受体A（SRA），一种主要在骨髓细胞上表达的模式识别分子，通过促进促血管生成的极化，肿瘤相关巨噬细胞我们的总体目标是全面了解以前未被认识到的SRA作为一个重要宿主的作用，所提出的研究的基本原理是，描绘SRA在响应于RT调节TME中的作用的基本机制具有开发新的靶向方法以减少临床中的癌症复发的潜力。我们将通过追求3个具体目标来验证我们的假设：1）使用临床相关模型系统的遗传、生物化学和细胞方法，建立SRA在增强RT后肿瘤血管系统恢复和随后复发中的关键作用; 2）确定SRA在使肿瘤相关巨噬细胞向交替活化的促血管生成表型倾斜中功能的分子和细胞基础;和3）证实靶向TME中的SRA以通过参与多价抗肿瘤机制来克服RT后复发的概念。鉴于SRA的既定免疫抑制功能，我们还将评估在TME中阻断SRA活性以提高基于RT和热休克蛋白的组合疗法的有效性的可行性。 TAM相关的SRA作为RT后治疗结果的关键肿瘤外在决定因素的概念，以及通过拮抗TME中的SRA以消除肿瘤血管重建并同时增强免疫功能来预防癌症复发的想法是创新的。拟议的研究是重要的，因为它预计将推进动态宿主-肿瘤相互作用的不同方面的理解和它们的影响，在改善肿瘤对RT的反应。从这些研究中获得的见解将促进合理设计的多模态治疗，以减少RT后的治疗失败。

DESCRIPTION (provided by applicant): 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.