Innate Metabolic MRI of Macrophage Infiltration in Prostate Cancer

 描述(申请人提供)：免疫细胞间质渗透与多种癌症的进展有关，包括前列腺癌。免疫疗法寻求促进这些浸润性细胞的积累或耗尽，以抑制肿瘤生长，并加强放射治疗。肿瘤相关巨噬细胞的存在与临床转归呈负相关，肿瘤相关巨噬细胞的缺失可提高治疗效果。虽然目前尚不清楚是什么原因导致巨噬细胞在肿瘤中聚集，但众所周知，决定巨噬细胞渗透的一个重要因素是组织铁负荷，因为组织铁代谢的高水平使其产生清除铁的免疫反应。我们的长期目标是利用免疫系统的这一特征，通过新的定量方法来改善治疗结果和成像免疫细胞渗透。这项建议的总体目标是在铁(III)的控制下监测一系列生理和治疗条件下的巨噬细胞渗透，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改进和补充我们正在使用的MRI、组织学、临床前治疗和免疫学技术，以揭示前列腺癌巨噬细胞免疫反应的驱动因素。已经安排了动手培训和与MSKCC实验室的合作(见支持函)，以确保提案的成功。我们建议检验两个假设：(1)铁在肿瘤中的积聚支持肿瘤相关巨噬细胞的渗透和它们向成瘤状态的极化；(2)通过螯合抑制巨噬细胞的渗透可以加强T细胞靶向免疫治疗和放射治疗，从而更有效地抑制肿瘤生长。确定铁在免疫细胞渗透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和组织学的可翻译组合来测量巨噬细胞的渗透在监测辐射效应方面具有很高的诊断意义。 和免疫癌症疗法。

 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.