Innate Metabolic MRI of Macrophage Infiltration in Prostate Cancer

前列腺癌巨噬细胞浸润的先天代谢 MRI

• 批准号: 9123058
• 负责人: Avigdor Leftin
• 金额: $ 6.2万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9123058
• 关键词: Affinity; Animal Cancer Model; Biological; Biological Markers; Biophysics; Cells; Chelation Therapy; Clinical; Collaborations; Comprehensive Cancer Center; Contrast Media; Data; Dependence; Detection; Diagnostic; Diet; Dietary Iron; Disease; Ensure; Exposure to; Goals; Hand; Histology; Image; Immune; Immune response; Immune system; Immunologic Techniques; Immunotherapy; Infiltration; Iron; Iron Chelation; Label; Laboratories; Letters; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Measures; Memorial Sloan-Kettering Cancer Center; Metabolic; Metabolism; Molecular; Monitor; Outcome; Outcome Study; Phenotype; Physiological; Probability; Process; Prostate Cancer therapy; Radiation; Radiation therapy; Research; Research Training; Role; Staging; T-Lymphocyte; Techniques; Testing; Therapeutic; Therapeutic Effect; Tissues; Training; Tumorigenicity; antitumor effect; cancer therapy; cancer type; career; chelation; experience; feeding; improved; in vivo; innovation; iron metabolism; macrophage; meetings; novel; pre-clinical; pre-clinical therapy; prostate cancer model; public health relevance; quantitative imaging; radiation effect; radiation response; response; skills; success; therapeutic biomarker; therapeutic target; therapy outcome; treatment response; tumor; tumor growth; tumor microenvironment; tumorigenic

 DESCRIPTION (provided by applicant): Stromal infiltration of immune cells is implicated in the progression of many types of cancer, including prostate cancer. Immune therapies seek to either promote the accumulation or depletion of these infiltrating cells to inhibit tumor growth an enhance radiation therapy. The presence of tumor associated macrophages is associated with negative clinical outcome, and their depletion can improve therapeutic response. While it is unknown what causes macrophage accumulation in tumors, it is generally known that an important factor determining macrophage infiltration is tissue iron load because their high innate iron metabolism primes them towards an iron scavenging immune response. Our long-term goal is to exploit this feature of the immune system to improve therapeutic outcomes and image immune cell infiltration with new quantitative approaches. The overall objective of this proposal is to monitor macrophage infiltration over a range of physiological and therapeutic conditions under control of iron (III) bringing us closer to this long term goal. The rationale for the proposd research training is to refine, and add to the MRI, histological, preclinical therapy, and immunological techniques we are using to uncover drivers of macrophage immune response in prostate cancer. Arrangements have been made for hands on training and collaborations with laboratories at MSKCC (see letters of support) to ensure the proposal's success. We propose to test two hypotheses: (1) iron accumulation in tumors supports infiltration of tumor-associated macrophages and their polarization towards a tumorigenic state, and (2) inhibiting macrophage infiltration using chelation can enhance T cell targeted immune therapy and radiation to more effectively inhibit tumor growth. Identifying iron's role in immune cell infiltration can fill a neded gap in our understanding of immune response in prostate cancer leading to better therapies. Further, using the translatable combination of MRI and histology to measure macrophage infiltration has high diagnostic significance in the context of monitoring the effects of radiation and immune cancer therapy.

 描述（由申请人提供）：免疫细胞的基质浸润与许多类型的癌症（包括前列腺癌）的进展有关。免疫疗法寻求促进这些浸润细胞的积累或消耗以抑制肿瘤生长并增强放射疗法。肿瘤相关巨噬细胞的存在与阴性临床结果相关，并且它们的消耗可以改善治疗反应。虽然尚不清楚是什么导致巨噬细胞在肿瘤中积聚，但通常已知决定巨噬细胞浸润的重要因素是组织铁负荷，因为它们的高先天铁代谢使它们朝向铁清除免疫应答。我们的长期目标是利用免疫系统的这一特征来改善治疗效果，并利用新的定量方法对免疫细胞浸润进行成像。该提案的总体目标是在铁（III）的控制下监测一系列生理和治疗条件下的巨噬细胞浸润，使我们更接近这一长期目标。拟议的研究培训的基本原理是完善和增加MRI，组织学，临床前治疗和免疫学技术，我们正在使用这些技术来揭示前列腺癌中巨噬细胞免疫反应的驱动因素。已经安排了实际操作培训和与MSKCC实验室的合作（见支持信），以确保该提案的成功。我们提出测试两个假设：（1）肿瘤中的铁积累支持肿瘤相关巨噬细胞的浸润及其向致瘤状态的极化，以及（2）使用螯合抑制巨噬细胞浸润可以增强T细胞靶向免疫治疗和放射，以更有效地抑制肿瘤生长。确定铁在免疫细胞浸润中的作用可以填补我们对前列腺癌免疫反应理解的空白，从而获得更好的治疗方法。此外，使用MRI和组织学的可转换组合来测量巨噬细胞浸润在监测辐射效应的背景下具有高诊断意义 和免疫癌症治疗。