Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival

Departments of Bioengineering and Medical Genetics, University of Washington, Seattle, WA 98195.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2013; 110(40). DOI: 10.1073/pnas.1312197110
Source: PubMed


Most current cancer therapies focus on killing malignant cells, but these cells are often genetically unstable and can become resistant to chemotherapy. Tumor-associated macrophages (TAMs) facilitate disease progression by promoting angiogenesis and tumor cell growth, as well as by suppressing the adaptive immune response. TAMs are therefore potential targets for adjuvant anticancer therapies. However, resident macrophages are critical to host defense, and preferential ablation of TAMs remains challenging. Macrophage activation is broadly categorized as classically activated, or M1, and alternatively activated, or M2, and TAMs in the tumor microenvironment have been shown to adopt the anti-inflammatory, M2-like phenotype. To date, there are no methods for specific molecular targeting of TAMs. In this work, we report the discovery of a unique peptide sequence, M2pep, identified using a subtractive phage biopanning strategy against whole cells. The peptide preferentially binds to murine M2 cells, including TAMs, with low affinity for other leukocytes. Confocal imaging demonstrates the accumulation of M2pep in TAMs in vivo after tail vein injection. Finally, tail vein injection of an M2pep fusion peptide with a proapoptotic peptide delays mortality and selectively reduces the M2-like TAM population. This work therefore describes a molecularly targeted construct for murine TAMs and provides proof of concept of this approach as an anticancer treatment. In addition, M2pep is a useful tool for murine M2 macrophage identification and for modulating M2 macrophages in other murine models of disease involving M2 cells.

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    • "On the other hand, it is known that the control of macrophage activity in tumors is important for effective tumor treatment.28,29 If the type of tumor macrophages that engulf CNHs were known, then new approaches for the treatment of tumors would be easier to develop.30,31 "
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    • "The recent report showed that M2pep, a peptide, can preferentially binds to M2 macrophages with low affinity for other leukocytes. Systemical administration of an M2pep fusion peptide with a proapoptotic peptide specifically reduced M2-like macrophages (77). A combination of CpG oligodeoxynucleotides and an IL-10 receptor-specific antibody switched TAMs from an M2 to an M1 type and triggered an innate response that was able to cure the majority of mice bearing large tumors (78). "
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