Abstract
Iron deposits are a phenotypic trait of tumor-associated macrophages (TAMs). Histological iron imaging and contrast-agent free magnetic resonance imaging (MRI) can detect these deposits, but their presence in human cancer, and correlation with immunotherapeutic response is largely untested. Here, primarily using these iron imaging approaches, we evaluated the spatial distribution of polarized macrophage populations containing high endogenous levels of iron in preclinical murine models and human breast cancer, and used them as metabolic biomarkers to correlate TAM infiltration with response to immunotherapy in preclinical trials. Macrophage-targeted inhibition of the colony stimulating factor 1 receptor (CSF1R) by immunotherapy was confirmed to inhibit macrophage accumulation and slow mammary tumor growth in mouse models while also reducing hemosiderin iron-laden TAM accumulation as measured by both iron histology and in vivo iron MRI (FeMRI). Spatial profiling of TAM iron deposit infiltration defined regions of maximal accumulation and response to the CSF1R inhibitor, and revealed differences between microenvironments of human cancer according to levels of polarized macrophage iron accumulation in stromal margins. We therefore demonstrate that iron deposition serves as an endogenous metabolic imaging biomarker of TAM infiltration in breast cancer that has high translational potential for evaluation of immunotherapeutic response.
Highlights
In most cancers, macrophage infiltration is linked to negative clinical outcomes such as poor survival, metastatic dissemination, and evasion of anti-tumor immune mechanisms[1,2,3,4]
As proof-of-concept, we directly compared histological sections stained for iron using Prussian blue that is specific for hemosiderin-laden macrophages (HLMs) (Fig. 1a), with iron maps generated by ex vivo FeMRI-microscopy (Fig. 1b) of co-registered tissue sections obtained from an orthotopic TS1 breast cancer model used commonly in tumor-associated macrophages (TAMs) research whose tumors are promoted under control of the murine mammary tumor virus which drives expression of the mammary gland specific polyoma virus middle T-antigen (MMTVPyMT)[45,46,47,48,49]
We interrogated the spatial distribution of the HLMs in the histological and FeMRI iron maps to compare these measurements as a score of TAM infiltration
Summary
Macrophage infiltration is linked to negative clinical outcomes such as poor survival, metastatic dissemination, and evasion of anti-tumor immune mechanisms[1,2,3,4]. By recognizing the tendency of macrophages to metabolically accumulate hemosiderin—which generates high-iron contrast akin to that produced using iron nanoparticle injections40 —microscopic deposits of these cells can be quantified in terms of their abundance and spatial distribution by MRI and histology without contrast agents according to their innate iron metabolism While these prior studies associated HLMs with TAMs and suggest that they can be used as probes of TAM infiltration to gauge efficacy of immune therapy, here we define the spatial correlations of these metabolically-unique TAM infiltrates with immunotherapy response, and prospectively characterize their distribution in human breast cancer using histological iron imaging in order to support the translation of such combination metabolic iron imaging and therapy approaches to the clinic
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