Potential PET tracers for imaging of tumor-associated macrophages

Abstract

The increasing incidence of cancer over the years is one of the most challenging problems in healthcare. As cancer progresses, the recruitment of several immune cells is triggered. Infiltration of tumor-associated macrophages (TAMs) is correlated with poor patient prognosis. Since TAMs constitute a big portion of the tumor mass, targeting these cells seems to be an attractive approach for cancer immunotherapy. Additionally, TAM assessment using non-invasive imaging techniques, such as positron emission tomography (PET), might provide a better understanding of the role of TAMs in cancer, and a means for tumor profile characterization, patient selection for individualized immunotherapy and treatment monitoring. Imaging of TAMs using PET tracers is still in its infancy. TAMs have several characteristics that could be exploited as potential targets for imaging. Various PET tracers for these TAM biomarkers have been developed, although often in the context of (neuro)inflammatory diseases rather than cancer. Since macrophages in inflammatory diseases express similar biomarkers as TAMs, these PET tracers could potentially also be applied for the assessment of TAMs in the tumor microenvironment. Therefore, the present review provides an overview of the TAM biomarkers, for which potential PET tracers are available and discusses the status of these tracers.

Keywords: M1-like; M2-like; PET imaging; Tumor microenvironment; Tumor-associated macrophages.

Fig. 1

The main biomarkers expressed by TAM phenotypes, for which PET tracers are available. For each biomarker, the available PET tracers are indicated. CSF-1R: colony stimulating factor 1 receptor; CD: cluster of differentiation; CCR2: C–C chemokine receptor type 2; FR: folate receptor; Arg1: arginase 1; IL: interleukin; TNF-α: tumoral necrose factor α; TGF-β: transforming growth factor β

Fig. 2

Structures of representative receptor ligands of the CSF-1R. The positions of the CSF-1R ligands that have been radiolabeled and evaluated as candidate PET tracers are highlighted in red. CSF-1R: colony stimulating factor 1 receptor

Fig. 3

Structures of representative candidate tracers for the CD206 receptor

Fig. 4

Representative in vivo PET/CT images of [⁶⁴Cu]Cu@CuOx-ECL1i. Images of [⁶⁴Cu]Cu@CuOx-ECL1i in KPPC mice, KPPC mice with 50-fold blocking dose, and [⁶⁴Cu]Cu@CuOx-NT in KPPC mice were performed at 24 h post injection (yellow arrow: pancreas/pancreatic tumor). Reprinted (adapted) with permission from X. Zang et al. ACS Nano 2021 (Zhang et al. 2021). Copyright © 2021 American Chemical Society

Fig. 5

Structures of representative candidate tracers for FRβ. FRβ: folate receptor β

Fig. 6

Structures (a) and PET images (b) of representative candidate tracers for arginase. PET images at 40–90 min post injections of [¹⁸F]FMARS and [¹⁸F]FBMARS in PC3 tumor (arrows; axial, coronal, and sagittal views from top to bottom) of mice without (control) and with coinjection of ABH (5 mM). ABH: (2(S)-amino-6-boronohexanoic acid. This research was originally published in JNM. G.S. Clemente, et al. J. Nucl. Med. 2021 (Clemente et al. 2021). Copyright © 2021 by the Society of Nuclear Medicine and Molecular Imaging