PET Imaging of Tumor-Associated Macrophage Dynamics and Response to Clinical Treatment for Potential Translation.

Tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment (TME). The abundance and distribution of TAMs significantly affect the immune responses of TME to determine the tumor progression and treatment response of solid tumors such as head and neck squamous cell carcinoma (HNSCC). Molecular characterization of human HNSCC specimens and mouse models has identified CD163 as a unique biomarker for TAMs in HNSCC. The goal of this study was to determine the dynamic changes of CD163-positive TAMs in HNSCC progression and treatment response to assess the potential of a CD163 targeted radiotracer, 64Cu-ICT-01, in detecting CD163-positive TAMs for translation in HNSCC. Methods: We assessed the capability of 64Cu-ICT-01 for noninvasive imaging of CD163-positive TAMs using PET. We determined its targeting specificity in multiple mouse HNSCC models to track the progression of tumors. We assessed its sensitivity in tracking variations of CD163-positive TAMs and correlation with tumor volumes after clinical treatment. We also measured its binding to CD163-positive TAMs upregulated on human HNSCC tissues. Results: 64Cu-ICT-01 PET specifically determined the spatiotemporal distribution of CD163-positive TAMs in a MOC1 cell line model and patient-derived xenograft HNSCC models. CD163 PET sensitively tracked the dynamics of CD163-positive TAMs after clinical treatment. Its tumor binding correlated with CD163 expression levels and the volumes of tumors. In human HNSCC specimens, 64Cu-ICT-01 showed strong and specific binding to human CD163. Conclusion: 64Cu-ICT-01 demonstrated accurate targeting of CD163 in both mouse tumor models and human HNSCC tissues. CD163 PET has great potential to be a noninvasive biomarker to measure TAM activities within TME, monitor treatment response, and optimize treatment strategy.