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Tumor development and growth, as well as metastatic spread, are strongly influenced by various, mostly innate, immune cells, which are recruited to the tumor site and driven to establish a specific tumor-supportive microenvironment. The contents of this microenvironment, such as myeloid cells, are a major factor in the overall prognosis of malignant disease, addressed by a constantly growing armament of therapeutic interventions targeting tumor-supportive immune cells. Current clinical imaging has long ignored the growing need for diagnostic approaches addressing these microenvironmental contents-approaches enabling a sensitive and specific classification of tumor immune crosstalk and the resulting tumor-associated immune cell activity. In this focus article we review the present status of, and promising developments in, the in vivo molecular imaging of tumor immune components designed to allow for inferences to be made on the cross-talk between tumor cells and the immune system. Current imaging modalities based on the infiltrating cell types are briefly discussed., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Unlabelled: Locoregional recurrence of breast cancer poses significant clinical problems because of frequent inoperability once the chest wall is involved. Early detection of recurrence by molecular imaging agents against therapeutically targetable receptors, such as c-Met, would be of potential benefit. The aim of this study was to assess (18)F-AH113804, a peptide-based molecular imaging agent with high affinity for human c-Met, for the detection of early-stage locoregional recurrence in a human basal-like breast cancer model, HCC1954., Methods: HCC1954 tumor-bearing xenograft models were established, and (18)F-AH113804 was administered. Distribution of radioactivity was determined via PET at 60 min after radiotracer injection. PET and CT images were acquired 10 d after tumor inoculation, to establish baseline distribution and uptake, and then on selected days after surgical tumor resection. CT images and caliper were used to determine the tumor volume. Radiotracer uptake was assessed by (18)F-AH113804 PET imaging. c-Met expression was assessed by immunofluorescence imaging of tumor samples and correlated with (18)F-AH113804 PET imaging results., Results: Baseline uptake of (18)F-AH113804, determined in tumor-bearing animals after 10 d, was approximately 2-fold higher in the tumor than in muscle tissue or the contralateral mammary fat pad. The tumor growth rate, determined from CT images, was comparable between the animals with recurrent tumors, with detection of tumors of low volume (<10 mm(3)) only possible by day 20 after tumor resection. (18)F-AH113804 PET detected local tumor recurrence as early as 6 d after surgery in the recurrent tumor-bearing animals and exhibited significantly higher (18)F-AH113804 uptake (in comparison to mammary fatty tissue), with a target-to-background (muscle) ratio of approximately 3:1 (P < 0.01). The c-Met expression of individual resected tumor samples, determined by immunofluorescence, correlated with the respective (18)F-AH113804 imaging signals (r = 0.82, P < 0.05)., Conclusion: (18)F-AH113804 PET provides a new diagnostic tool for the detection of c-Met-expressing primary tumor and has potential utility for the detection of locoregional recurrence from an early stage., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: Tumors recruit and reprogram immune cells to support tumor development and spread, the most prominent among them being of monocytic origin such as tumor-associated macrophages (TAM) or myeloid-derived suppressor cells (MDSC). The alarmin S100A8/A9 has been implicated in the induction of TAM and MDSC. We assessed S100A9 as a molecular imaging marker for the activity of tumor-associated immune cells in a syngeneic murine breast cancer model. S100A9 could serve as a surrogate marker for tumor immune crosstalk as a function of malignancy, providing a tool with the potential for both basic research in tumor immunology and clinical stratification of patients., Methods: BALB/c mice were inoculated with murine breast cancer cells of common origin but different metastatic capability. At different times during tumor development, optical imaging was performed using a S100A9-specific probe to visualize activated monocytes. To further explore the impact of tumor-educated monocytes, splenic myeloid cells were isolated from either healthy or tumor-bearing animals and injected into tumor-bearing mice. We analyzed the effect of the cell transfer on immune cell activity and tumor development., Results: We could prove S100A9-driven imaging to sensitively and specifically reflect monocyte activity in primary tumor lesions. The imaging results were corroborated by histology and fluorescence-activated cell sorting analyses. In a prospective experiment, S100A9 imaging proved indicative of the individual tumor growth, with excellent correlation. Moreover, we could show that the monocyte activity as depicted by S100A9 activity in the primary tumor lesion mirrored the tumor's metastatic behavior. Treatment with tumor-primed splenic monocytes induced increased tumor growth, accompanied by an augmented infiltration of activated myeloid cells (MDSC and TAM) into the tumor. The consecutive S100A9 expression as depicted by in vivo imaging was significantly increased., Conclusion: S100A9 proved to be a sensitive and specific marker for the activity of tumor-associated immune cells. To our knowledge, S100A9 imaging represents a first in vivo imaging approach for the estimation of recruitment and activity of tumor-associated myeloid immune cells. We demonstrated the potential value of this imaging approach for prediction of local and systemic tumor development., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)