Mifamurtide and TAM-like macrophages: effect on proliferation, migration and differentiation of osteosarcoma cells

Abstract

Tumor-associated macrophages and their alternative activation states together with cytokines and growth factors trapped in tumor microenvironment contribute to the progression of OS. In contrast to other tumor types, M2 polarized macrophages, reduce metastasis and improve survival in osteosarcoma patients. Mifamurtide is an immunomodulatory drug given together with standard adjuvant chemotherapy in high-grade osteosarcoma to improve outcome. Macrophages obtained from peripheral blood mononucleated cells of healthy donors and MG63 cells were cultured alone and together, and treated with Mifamurtide. We analyzed the effects of Mifamurtide on macrophage polarization and on MG63 proliferation, migration and differentiation, evaluating the expression of M1/M2 and osteoblast markers and molecules involved in metastasis and proliferation pathways. Our data suggest that Mifamurtide, switching macrophage polarization towards a TAM-like intermediate M1/M2 phenotype, may modulate the delicate balance between pro-inflammatory and immunomodulatory macrophage functions. Moreover, Mifamurtide may inhibit the cellular proliferation and induce the tumor cell differentiation, probably through the down regulation of pSTAT3, pAKT and IL-17R.

Signature based on immune-related LncRNA can predict overall survival of osteosarcoma patients

“…At the same time, the inhibitory effect of activated M1-like macrophages on the growth of osteosarcoma cells is mediated by soluble factors [58]. The latest research shows that Mifamurtide regulates the function of macrophages by converting the polarization of macrophages to a TAM-like intermediate M1/M2 phenotype, thereby inhibiting the proliferation of osteosarcoma cells [59]. Consistent with previous results, our results show that patients in the low-risk group have a higher abundance of macrophage in ltration.…”

Tumor-Associated Macrophages in Osteosarcoma: From Mechanisms to Therapy

“…In phase II clinical trials mifamurtide induced the infiltration of activated macrophages into OS lung tissue metastases [ 143 ] with a marked difference in disease progression and overall survival [ 144 ] and that the mifamurtide-mediated M1-TAMs antitumor activity required IFN-γ [ 145 ]. Punzo et al demonstrated that, by switching macrophage polarization towards a TAM-like intermediate M1/M2 phenotype, mifamurtide may work by modulating macrophage functions and inhibit OS proliferation [ 102 ]. In order to enhance the activation of the immune response, the European Medical Agency (EMA) has approved the use of mifamurtide, as an adjuvant in combination with chemotherapy, for the treatment of OS patients [ 146 ].…”

Effects of Eltrombopag on In Vitro Macrophage Polarization in Pediatric Immune Thrombocytopenia

“…Macrophages are immune cells with a key role in inflammatory processes [ 8 , 9 , 10 ], and they are present in two distinct states of activation: the classically activated macrophages (M1) and the alternatively activated macrophages (M2) [ 9 , 10 , 11 ]. While M1 exert pro-inflammatory, anti-tumor, and anti-microbial properties, releasing pro-inflammatory cytokines [ 8 , 9 , 10 , 11 ], M2 show anti-inflammatory and immunosuppressive functions, releasing anti-inflammatory cytokines and promoting tumor progression [ 8 , 9 , 10 , 11 ]. The prevalence of M1 in ITP is responsible for both disease pathogenesis and impairment in inflammatory and immune responses [ 8 , 9 , 10 ].…”

“…M1 macrophages are activated by Tumor Necrosis Factor-α (TNF-α), Interferon-γ (IFN-γ), and bacterial lipopolysaccharide (LPS). They exert pro-inflammatory, anti-tumor, and anti-microbial functions, releasing high levels of pro-inflammatory cytokines, such as TNF-α, Interleukin-6 (IL-6), Interleukin-1β (IL-1β), and Nitric Oxide Synthase (iNOS) [ 8 , 9 , 10 , 11 ]. M2 macrophages are activated by Interleukin-4 (IL-4), Interleukin-13 (IL-13), Interleukin-10 (IL-10), and by Phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin (PI3K-Akt-mTOR) signaling pathway.…”

“…M2 macrophages are activated by Interleukin-4 (IL-4), Interleukin-13 (IL-13), Interleukin-10 (IL-10), and by Phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin (PI3K-Akt-mTOR) signaling pathway. They exert anti-inflammatory and immunosuppressive activities, by releasing anti-inflammatory cytokines, such as IL-10 and Transforming Growth Factor-β (TGF-β), and have also pro-angiogenic and pro-fibrotic properties, promoting tumor progression [ 8 , 9 , 10 , 11 ]. M2 alternatively activated macrophages also express Cluster of Differentiation 206 (CD206).…”