Clinical Translation of Neutrophil Imaging and Its Role in Cancer

Abstract

Neutrophils are the first line of defense against pathogens and abnormal cells. They regulate many biological processes such as infections and inflammation. Increasing evidence demonstrated a role for neutrophils in cancer, where different subpopulations have been found to possess both pro- or anti-tumorigenic functions in the tumor microenvironment. In this review, we discuss the phenotypic and functional diversity of neutrophils in cancer, their prognostic significance, and therapeutic relevance in human and preclinical models. Molecular imaging methods are increasingly used to probe neutrophil biology in vivo, as well as the cellular changes that occur during tumor progression and over the course of treatment. This review will discuss the role of neutrophil imaging in oncology and the lessons that can be drawn from imaging in infectious diseases and inflammatory disorders. The major factors to be considered when developing imaging techniques and biomarkers for neutrophils in cancer are reviewed. Finally, the potential clinical applications and the limitations of each method are discussed, as well as the challenges for future clinical translation.

Keywords: Cancer; Imaging; Immunotherapy; Infection; Inflammation; MRI; Neutrophils; Optical; PET; SPECT.

Fig. 1.

Tumor-associated neutrophils exhibit phenotypic diversity over the course of cancer progression. Oncogenic signaling events which regulate the expression of TGF-β and IFN-β govern the plasticity switch between the anti-tumoral (N1) and pro-tumoral (N2) phenotypes. Image created with BioRender.com (agreement number MZ22VWEC70)

Fig. 2.

Longitudinal imaging using IVM in Catchup mice implanted with small tumors at the ear pinnae showed early effects of CXCR2 blockade on tumor recruitment of tdTomato⁺ neutrophils on day 0 but not in the later time points at day 3 and day 6 as the disease progressed. Images reproduced with permission from [38]

Fig. 3.

Cellular tracking of changes in ¹⁹F signal and inflammation resolution over 20 days in an LPS-induced model. Images reproduced with permission from [40]

Fig. 4.

The cellular kinetics and molecular events involved in neutrophil function in cancer can be imaged using radiopharmaceuticals developed originally for imaging infection and inflammatory disorders. A Neutrophils can be directly labeled with lipophilic radiopharmaceuticals such as [¹¹¹In]In-tropolone for cellular tracking in vivo [41]. B Non-invasive detection of neutrophils based on the expression of its specific cell surface antigen activation marker CD15 has been performed clinically using [^99mTc]Tc-fanolesomab [70]. C Neutrophil migration to sites of inflammation has been studied using the radiolabeled chemokine [^99mTc]Tc-CXCL8 [42]. D Activation of neutrophils in inflamed tissues can be visualized non-invasively by imaging the activity of proteolytic enzymes such as myeloperoxidase with the small molecule [¹⁸F]F-MAPP [43]. E The role of complement activation in the inflammatory processes of neutrophil recruitment and activation and dose-dependent changes with treatment can be probed with a radiolabeled natural ligand of C3d complement receptor-2, [^99mTc]Tc-rCR2 [88]. F The involvement of neutrophils in immunometabolism and tumor metabolic immunosuppression can be imaged using a radiofluorinated small molecule inhibitors of arginase-1, [¹⁸F]FBMARS [101]. Images reproduced with permission from [–43, 70, 88], and [101]