Host-tumor interactions and cancer relapse after radiation therapy

描述(申请人提供)：尽管放射治疗(放射治疗，例如图像引导和强度调节放射治疗)的进步导致了治疗结果的改善，但对于一些癌症来说，克服肿瘤复发仍然是一个挑战，因为放射治疗是一种重要的治疗方式。人们越来越认识到恶性肿瘤细胞和未转化的宿主细胞(例如免疫细胞、内皮细胞)之间的动态相互作用不仅决定了癌症的行为(例如侵袭和转移)，而且决定了包括RT在内的治疗反应。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放疗后复发的影响仍有待阐明。基于我们的初步数据，这一应用中的中心假设是清道夫受体A(SRA)，一种主要表达于髓系细胞的模式识别分子，通过促进肿瘤相关巨噬细胞(TAM)的极化和放疗后的肿瘤血管重建而促进肿瘤复发。我们的总体目标是全面了解SRA作为一个重要的宿主因子在调节动态髓系细胞-肿瘤串扰和肿瘤对RT的反应中所扮演的以前未知的角色。这项拟议研究的基本原理是，阐明SRA在调节TME对RT的反应中的基本作用机制，有可能开发出新的靶向方法，以减少临床上的癌症复发。我们将通过追求3个特定目标来验证我们的假设：1)利用遗传学、生化和细胞学方法，结合临床相关模型系统，建立SRA在促进放疗后肿瘤血管恢复及后续复发中的关键作用；2)确定SRA功能在扭曲肿瘤相关巨噬细胞向交替激活的促血管生成表型倾斜方面的分子和细胞基础；以及3)验证在TME中靶向SRA的概念，通过参与多价抗肿瘤机制来克服放疗后复发。鉴于SRA的免疫抑制功能已经确立，我们还将评估阻断TME中SRA活性以提高基于RT和热休克蛋白的联合治疗的有效性的可行性。相关的SRA作为放疗后治疗结果的关键、肿瘤外部决定因素的概念，以及通过在TME中拮抗SRA以消除肿瘤血管重建并同时增强免疫功能来防止癌症复发的想法是创新的。这项拟议的研究具有重要意义，因为它有望促进对动态宿主-肿瘤相互作用的不同方面的理解，以及它们在改善肿瘤对放射治疗的反应方面的意义。从这些研究中获得的见解将有助于合理设计多模式治疗以减少放疗后的治疗失败。

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.