Tumor-Associated Macrophages in Osteosarcoma: From Mechanisms to Therapy

Abstract

Osteosarcomas (OSs) are bone tumors most commonly found in pediatric and adolescent patients characterized by high risk of metastatic progression and recurrence after therapy. Effective therapeutic management of this disease still remains elusive as evidenced by poor patient survival rates. To achieve a more effective therapeutic management regimen, and hence patient survival, there is a need to identify more focused targeted therapies for OSs treatment in the clinical setting. The role of the OS tumor stroma microenvironment plays a significant part in the development and dissemination of this disease. Important components, and hence potential targets for treatment, are the tumor-infiltrating macrophages that are known to orchestrate many aspects of OS stromal signaling and disease progression. In particular, increased infiltration of M2-like tumor-associated macrophages (TAMs) has been associated with OS metastasis and poor patient prognosis despite currently used aggressive therapies regimens. This review aims to provide a summary update of current macrophage-centered knowledge and to discuss the possible roles that macrophages play in the process of OS metastasis development focusing on the potential influence of stromal cross-talk signaling between TAMs, cancer-stem cells and additional OSs tumoral microenvironment factors.

MNAT1 promotes proliferation and the chemo-resistance of osteosarcoma cell to cisplatin through regulating PI3K/Akt/mTOR pathway

“…Although in-depth knowledge has been made in the diagnosis and treatment strategies of OS, due to its delayed diagnosis and lack of effective treatment strategies, its mortality rate remains high [ 3 , 11 ]. Therefore, it is essential to have a thorough understanding of the underlying mechanisms of OS carcinogenesis in order to develop new OS treatment strategies.…”

Osteosarcoma Pathogenesis Leads the Way to New Target Treatments

“…Not only mifamurtide (by promoting a TAM polarization towards an intermediate M1/M2 phenotype), but also all trans retinoic acid, esculetin, zoledronate, natalizumab, nivolumab, and pembrolizumab may have the capacity of shaping TAM polarization and their function [NR]. Recent evidence also suggests that blocking PI 3-kinase γ, ERK5-MAPK, and c-Maf pathways (using, for example, nanoparticles loaded with its specific inhibitors) may promote repolarization of TAM to an M1 phenotype with subsequent antitumor and anti-metastatic effects [ 94 ]. Finally, the use of chimeric antigen receptor macrophages may also have positive effects on TAM polarization [ 94 ] [NR].…”

“…Recent evidence also suggests that blocking PI 3-kinase γ, ERK5-MAPK, and c-Maf pathways (using, for example, nanoparticles loaded with its specific inhibitors) may promote repolarization of TAM to an M1 phenotype with subsequent antitumor and anti-metastatic effects [ 94 ]. Finally, the use of chimeric antigen receptor macrophages may also have positive effects on TAM polarization [ 94 ] [NR].…”

Will Next-Generation Immunotherapy Overcome the Intrinsic Diversity and Low Immunogenicity of Sarcomas to Improve Clinical Benefit?

“…One of the main challenges observed in immunotherapy is the inability to reliably predict patient response to treatment, thus there is a need for suitable biomarkers to more precisely inform treatment choices. Useful insights to achieve this goal may derive from a better understanding of the complex and heterogeneous TME characterising sarcomas [ 135 , 136 , 137 ]. A recent immunogenomic study including gene expression data from more than 850 sarcomas had identified three prognosis-related TME groups according to the extent of infiltration of 22 different immune cells [ 138 ].…”