Host-tumor interactions and cancer relapse after radiation therapy

放射治疗后宿主-肿瘤相互作用和癌症复发

• 批准号: 8776930
• 负责人: Xiang-Yang Shawn Wang
• 金额: $ 31.64万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8776930
• 关键词: Ablation; Address; Automobile Driving; Behavior; Biochemical; Biological Models; Cancer Patient; Cancer Relapse; Cell physiology; Cells; Clinic; Clinical; Combined Modality Therapy; Data; Development; Disease; Down-Regulation; Effectiveness; Employee Strikes; Endothelial Cells; Event; Failure; Genes; Genetic; Goals; Health; Heat shock proteins; Immune; Immune response; Immunosuppressive Agents; In Situ; Inflammation Mediators; Inflammatory; Injury; Integration Host Factors; Intensity-Modulated Radiotherapy; Lead; Malignant Neoplasms; Maps; Mediating; Mediator of activation protein; Mission; Modality; Molecular; Mus; Myeloid Cells; Neoplasm Metastasis; Normal tissue morphology; Outcome; Pathology; Patients; Pattern Recognition; Phenotype; Production; Protein Binding; Public Health; Radiation Oncology; Radiation therapy; Recovery; Recurrence; Regulation; Relapse; Research; Research Priority; Role; Signal Transduction; Testing; Therapeutic; Therapeutic Intervention; Tissues; Toxic effect; Treatment Failure; Treatment outcome; Tumor Cell Invasion; Vaccines; Vascular Endothelial Cell; Work; antitumor effect; base; cancer radiation therapy; cancer recurrence; clinically relevant; combinatorial; design; host neoplasm interaction; image guided; immune function; improved; innovation; insight; irradiation; macrophage; molecular dynamics; neoplastic cell; new therapeutic target; novel; prevent; radiation response; response; restoration; scavenger receptor; therapeutic effectiveness; therapeutic target; tumor; tumor immunology; tumor microenvironment; tumor progression

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.

描述（由申请人提供）：尽管放射治疗（RT，例如图像引导和强度调制 RT）的进步已经改善了治疗结果，但对于许多癌症来说，克服肿瘤复发仍然是一个挑战，其中 RT 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非转化宿主细胞（例如免疫细胞、内皮细胞）之间的动态相互作用不仅决定癌症行为（例如侵袭和转移），而且决定对治疗（包括放疗）的反应。然而，肿瘤微环境（TME）内分子和细胞相互作用的精确机制及其对放疗后复发的影响仍有待阐明。根据我们的初步数据，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、肿瘤相关巨噬细胞 (TAM) 的极化和放疗后肿瘤血运重建来促进肿瘤复发。我们的总体目标是全面了解 SRA 作为控制动态骨髓细胞-肿瘤串扰和肿瘤对 RT 反应的重要宿主因素的先前未被认识的作用。拟议研究的基本原理是，描绘 SRA 在调节 TME 响应 RT 方面的作用的基本机制，有可能开发新的靶向方法来减少临床癌症复发。我们将通过追求 3 个具体目标来检验我们的假设：1）利用遗传、生化和细胞方法以及临床相关模型系统，确定 SRA 在增强放疗后肿瘤脉管系统恢复和随后复发方面的关键作用； 2) 确定 SRA 功能的分子和细胞基础，使肿瘤相关巨噬细胞偏向于替代激活的促血管生成表型； 3) 验证 TME 中靶向 SRA 的概念，通过利用多价抗肿瘤机制来克服 RT 后复发。鉴于 SRA 已确定的免疫抑制功能，我们还将评估在 TME 中阻断 SRA 活性的可行性，以提高基于 RT 和热休克蛋白的组合疗法的有效性。 TAM 相关的 SRA 作为放疗后治疗结果的关键肿瘤外在决定因素，以及通过拮抗 TME 中的 SRA 来消除肿瘤血运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。拟议的研究意义重大，因为它有望促进对动态宿主-肿瘤相互作用的不同方面及其在改善肿瘤对放疗反应方面的影响的理解。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。