Abstract
Immune cells such as macrophages are drivers and biomarkers of most cancers. Scoring macrophage infiltration in tumor tissue provides a prognostic assessment that is correlated with disease outcome and therapeutic response, but generally requires invasive biopsy. Routine detection of hemosiderin iron aggregates in macrophages in other settings histologically and in vivo by MRI suggests that similar assessments in cancer can bridge a gap in our ability to assess tumor macrophage infiltration. Quantitative histological and in vivo MRI assessments of non-heme cellular iron revealed that preclinical prostate tumor models could be differentiated according to hemosiderin iron accumulation—both in tumors and systemically. Monitoring cellular iron levels during “off-label” administration of the FDA-approved iron chelator deferiprone evidenced significant reductions in tumor size without extensive perturbation to these iron deposits. Spatial profiling of the iron-laden infiltrates further demonstrated that higher numbers of infiltrating macrophage iron deposits was associated with lower anti-tumor chelation therapy response. Imaging macrophages according to their innate iron status provides a new phenotypic window into the immune tumor landscape and reveals a prognostic biomarker associated with macrophage infiltration and therapeutic outcome.
Highlights
The extent of immune cell infiltration in tumors is correlated with predicted therapeutic response and survival probability in many cancers, including prostate cancer (PCa)[1]
In addition to their function in the innate immune response, macrophages play key roles in recycling iron[12,13,14]. This is facilitated by the sequestration of iron(III) in ferritin protein aggregates known as hemosiderin in so-called hemosiderin laden macrophages (HLMs) that prevent depletion of limited body iron stores, and contribute to maintaining low equilibrium levels of cytotoxic chelatable free iron[12, 15, 16]
The fer granules were larger in Myc-CaP prostate tumors (p < 0.0001, Fig. 1d), and HLMs were larger in prostate tumors of the Myc-CaP model (p < 0.05, Fig. 1f), while both the size of fer granules and HLMs were similar in livers and spleens of the Myc-CaP and TRAMP-C2 animals (p > 0.05)
Summary
The extent of immune cell infiltration in tumors is correlated with predicted therapeutic response and survival probability in many cancers, including prostate cancer (PCa)[1]. Efforts to identify factors associated with the infiltrative pro-tumor behavior of macrophages have revealed numerous cytokine-signaling networks that regulate their function in the tumor microenvironment[7,8,9] Many of these fundamental insights into macrophage immune response have led to new immune therapies, which have shown promise in preclinical PCa models[10, 11]. Most of these therapeutic targets do not have corresponding endogenous, non-invasive in vivo imaging biomarkers requiring surrogate measures of treatment response often restricted to bulk imaging assessment of tumor burden, and measures of immune cells by invasive biopsy. We chose the Myc-CaP and TRAMP-C2 transgenic prostate cancer cell lines as two common orthotopically implantable in vivo models differing generally in iron background due to their syngeneic FVB/N and C57BL/6 syngeneic mouse hosts[50] in order to correlate the spatial distributions of iron deposits with systemic and anti-tumor response to chelation therapy in prostate cancer
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