Abstract
Tumor-associated macrophages (TAMs) expressing the multi-ligand endocytic receptor mannose receptor (CD206/MRC1) contribute to tumor immunosuppression, angiogenesis, metastasis, and relapse. Here, we describe a peptide that selectively targets MRC1-expressing TAMs (MEMs). We performed in vivo peptide phage display screens in mice bearing 4T1 metastatic breast tumors to identify peptides that target peritoneal macrophages. Deep sequencing of the peptide-encoding inserts in the selected phage pool revealed enrichment of the peptide CSPGAKVRC (codenamed “UNO”). Intravenously injected FAM-labeled UNO (FAM-UNO) homed to tumor and sentinel lymph node MEMs in different cancer models: 4T1 and MCF-7 breast carcinoma, B16F10 melanoma, WT-GBM glioma and MKN45-P gastric carcinoma. Fluorescence anisotropy assay showed that FAM-UNO interacts with recombinant CD206 when subjected to reducing conditions. Interestingly, the GSPGAK motif is present in all CD206-binding collagens. FAM-UNO was able to transport drug-loaded nanoparticles into MEMs, whereas particles without the peptide were not taken up by MEMs. In ex vivo organ imaging, FAM-UNO showed significantly higher accumulation in sentinel lymph nodes than a control peptide. This study suggests applications for UNO peptide in diagnostic imaging and therapeutic targeting of MEMs in solid tumors.
Highlights
Tumor-associated macrophages displaying a M2-like phenotype (M2 TAMs) play major roles in progression of solid tumors, including epithelial and mesenchymal tumors, glia-derived tumors, and melanoma[1]
We have previously shown that activated TAMs overexpress cell surface p32 protein, a molecule that can be targeted by LyP-1 peptide[12], its higher-affinity version TT113, and a low-molecular-weight peptidomimetic compound[14]
CSPGAKVRC peptide is enriched in phage display screens on peritoneal macrophages in breast cancer mice
Summary
Tumor-associated macrophages displaying a M2-like phenotype (M2 TAMs) play major roles in progression of solid tumors, including epithelial and mesenchymal tumors, glia-derived tumors, and melanoma[1]. M2-like TAMs increase in number after chemotherapy and contribute to tumor relapse[2,6] They limit the efficacy of chemotherapies[8] and support immunosuppressive microenvironment in tumors[9]. Cell surface p32 is expressed on activated TAMs, and on other types of cells in tumors, and does not allow specific targeting of M2-skewed macrophages (Säälik et al, unpublished). A nanobody that recognizes CD206 has been developed and its 99mTc and 18F-labeled versions have been used for PET imaging of MEMs in mice[19,20]. It is not known if the nanobody is internalized by the CD206-positive cells. We identify and characterize a peptide codenamed “UNO” that targets CD206 on MEMs across a spectrum of solid tumors of different types
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