Immunotherapies have emerged as an effective treatment option for immune-related diseases, such as cancer and inflammatory diseases. However, variations in patient responsiveness limit the broad applicability and success of these immunotherapies. Noninvasive whole-body imaging of the immune status of individual patients during immunotherapy could enable the prediction and monitoring of the patient's response, resulting in more personalized treatments. In this study, we developed a nanobody-based immunotracer targeting CD163, a receptor specifically expressed on macrophages. This anti-CD163 immunotracer bound to human and mouse CD163 with high affinity and specificity without competing for ligand binding. Furthermore, the tracer showed no unwanted immune cell activation and was nonimmunogenic. Upon radiolabeling of the anti-CD163 immunotracer, specific imaging of CD163⁺ macrophages using micro-single-photon emission computerized tomography/computed tomography or micro-positron emission tomography/CT was performed. The anti-CD163 immunotracer was able to stratify immunotherapy responders from nonresponders (NR) by visualizing differences in the intratumoral CD163⁺ TAM distribution in Lewis lung carcinoma-ovalbumin tumor-bearing mice receiving an anti-programmed cell death protein-1 (PD-1)/CSF1R combination treatment. Immunotherapy-responding mice showed a more homogeneous distribution of the PET signal in the middle of the tumor, while CD163⁺ TAMs were located at the tumor periphery in NR. As such, visualization of CD163⁺ TAM distribution in the tumor microenvironment could allow a prediction or follow-up of therapy response. Altogether, this study describes an immunotracer, specific for CD163⁺ macrophages, that allows same-day imaging and follow-up of these immune cells in the tumor microenvironment, providing a good basis for the prediction and follow-up of immunotherapy responses in cancer patients.

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