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.
The extent of infiltration of immune cells, such as macrophages, in tumors is an indicator of disease stage, predicted therapeutic response, and survival probability in many cancers including prostate cancer. New immune therapies seek to modulate cell infiltration to realize therapeutic gains alone, and in combination with radiation therapy. Here we exploit the metabolic dependence of tumor associated macrophages on iron (III) to enable their diagnostic detection with a label-free MRI technique, and deplete them from the tumor microenvironment with iron chelation to enhance therapeutic response to radiation and immune therapy.
| Leftin, Avigdor; Koutcher, Jason A (2018) Quantification of Nanoparticle Enhancement in Polarized Breast Tumor Macrophage Deposits by Spatial Analysis of MRI and Histological Iron Contrast Using Computer Vision. Contrast Media Mol Imaging 2018:3526438 |
| Leftin, Avigdor; Zhao, Huiyong; Turkekul, Mesru et al. (2017) Iron deposition is associated with differential macrophage infiltration and therapeutic response to iron chelation in prostate cancer. Sci Rep 7:11632 |
