Noninvasive Imaging of CD206-Positive M2 Macrophages as an Early Biomarker for Post-Chemotherapy Tumor Relapse and Lymph Node Metastasis

Abstract

Tumor relapse after initial regression post-chemotherapy is a major challenge in cancer treatment, as it usually leads to local-regional recurrence or inoperable distant metastasis. M2 macrophages diminish the tumor-inhibitory effect of chemotherapy and correlate with distant metastasis and poor prognosis. In this study, we investigated whether molecular imaging of M2 macrophages could serve as an early biomarker for tumor relapse after chemotherapy and tumor lymph node metastasis in preclinical mouse models. Methods: We developed M2 macrophage-targeted probes for near-infrared fluorescence (NIRF) imaging and single-photon emission computed tomography (SPECT) using an anti-CD206 monoclonal antibody. The specific targeting capacity and potential applications of the NIRF and SPECT probes were investigated in subcutaneous tumor and lymph node metastasis models of 4T1 murine breast cancer. Results: M2 macrophage infiltration was significantly increased in the 4T1 tumors that later underwent relapse but not in non-relapsing 4T1 tumors after cyclophosphamide treatment. Through NIRF imaging and SPECT using our synthesized probes, the infiltration of M2 macrophages in relapsing tumors and tumor lymph node metastasis could be sensitively detected. Importantly, early prediction of tumor relapse by molecular imaging of M2 macrophages resulted in an effective eradication of tumors upon combination with additional radiotherapy. Conclusion: Our findings demonstrate that M2 macrophage-targeted imaging allows for noninvasively predicting post-chemotherapy tumor relapse and sensitively detecting the metastatic lymph nodes in vivo. This imaging strategy could provide a better understanding of cancer progression, enable early prediction of tumor resistance, and have implications on the rational design of cancer therapeutics.

Characterization of macrophages infiltrating peri‐implantitis lesions

“…The current literature on macrophage polarization does not have a clear consensus on markers to identify M1 polarization and M2 polarization, and emerging data suggest an increased complexity on the differentiation of macrophages dependent on environmental cues. Few studies proposed staining protocols for activated macrophages with iNOS (He et al, ; Tang, Zhao, Lei, Chen, & Zhang, ), CCR7 (Wang, Li, Feng, Cheng, & Li, ) for detecting M1 phenotypes, while others used CD206 (Viniegra et al, ) (Lee et al, ; Nawaz et al, ; C. Zhang et al, ) or CD163 (Ham et al, ; Wang et al, ) for M2 phenotypes. The presence of subtypes of macrophage polarization like M2a, M2b, M2c, and M2d also remains to be defined in periodontal diseases.…”

“…Small sample size has elevated chances to incorporate unforeseen bias, and the statistical results must be interpreted carefully. Nawaz et al, 2017;C. Zhang et al, 2017) or CD163 (Ham et al, 2017;Wang et al, 2019) ies will help to shed light on the macrophage signature and their potential contribution to the transition of peri-implant mucositis into peri-implantitis.…”

Clinical Translation of [68Ga]Ga-NOTA-anti-MMR-sdAb for PET/CT Imaging of Protumorigenic Macrophages

“…Fluorescence imaging using more specific MMRtargeting agents has been reported using a full monoclonal anti-MMR antibody and using an MMR-binding peptide [20][21][22]. Recently, a 125 I-labeled monoclonal antibody was used for SPECT imaging [22]. These studies confirm the promise of specifically targeting MMR for the imaging of protumorigenic macrophages, but the use of sdAb offers multiple advantages compared to approaches using mAbs given their faster blood clearance and good tissue penetration characteristics.…”

“…Fluorescence imaging using more specific MMRtargeting agents has been reported using a full monoclonal anti-MMR antibody and using an MMR-binding peptide [20][21][22]. Recently, a 125 I-labeled monoclonal antibody was used for SPECT imaging [22].…”

Magnetic resonance imaging of stem cell–macrophage interactions with ferumoxytol and ferumoxytol‐derived nanoparticles

“…We cannot discriminate between M1 and M2 macrophages using ferumoxytol MRI. Alternatively, several investigators are developing nano‐probes that specifically target M1 macrophages (Shimizu et al, ) or M2 macrophages (C. Zhang et al, ). In addition, the nanoparticles themselves might change macrophage phenotype polarizations: we showed that high doses of ferumoxytol could activate macrophages and thereby cause intrinsic pro‐inflammatory effects (Zanganeh et al, ).…”