Abstract
Melanoma is an immunogenic tumor and a serious type of skin cancer. Tumor-associated macrophages (TAMs) express an M2-like phenotype and are involved in all stages of melanomagenesis; it is hence a promising target for cancer immunotherapy. We herein investigated whether melittin–dKLA inhibits the growth of melanoma by inducing apoptosis of M2-like macrophages. For the in vitro study, a conditioned medium of macrophages was prepared from M0, M1, or M2-differentiated THP-1 cells with and without melittin–dKLA. The affinity of melittin for M2 macrophages was studied with FITC (fluorescein isothiocyanate)-conjugated melittin. For the in vivo study, murine melanoma cells were inoculated subcutaneously in the right flank of mice, melittin–dKLA was intraperitoneally injected at 200 nmol/kg every three days, and flow cytometry analysis of TAMs was performed. Since melittin binds preferentially to M2-like macrophages, melittin–dKLA induced more caspase 3 expression and cell death in M2 macrophages compared with M0 and M1 macrophages and melanoma cells. Melittin–dKLA significantly inhibited the proliferation and migration of M2 macrophages, resulting in a decrease in melanoma tumor growth in vivo. The CD206+ M2-like TAMs were reduced, while the CD86+ M1-like TAMs were not affected. Melittin–dKLA is therapeutically effective against melanoma by inducing the apoptosis of M2-like TAMs.
Highlights
Melanoma develops in the pigment-producing cells and is the most serious among the types of skin cancer, which include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) [1]
To test differentiation of macrophages to M2 phenotype, the THP-1 cells were stimulated with LPS and IFN-γ for M1 and with IL-4 and IL-13 for M2, and the polarization of macrophages was determined through the expression of M2 macrophage markers, such as IL-10, tumor growth factor (TGF)-β, arginase-1, and CD206, and M1 macrophage markers, such as IL-12 and
PBS group tin–dKLA hasgroup an inhibitory effect onthe melanoma in (Figure vivo. 6F). These results suggest that melittin–dKLA has an inhibitory effect on melanoma in vivo
Summary
Melanoma develops in the pigment-producing cells and is the most serious among the types of skin cancer, which include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) [1]. Melanoma has been found to occur 1.5 times more frequently in men than in women; the prevalence before age 40 is higher in women than in men [4,5]. Treatments such as surgery, radiotherapy, and chemotherapy are successful, many patients with melanoma still die from distal metastasis because of the aggressive nature of this cancer [6]. The TME of melanoma is known to contain various types
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