Modulatory effects of adiponectin on the polarization of tumor-associated macrophages

Abstract

© 2015 UICC. The plasticity of macrophages with selective functional phenotypes partially arises in respective to their microenvironment. Tumor-associated macrophages (TAMs) may promote disease progression with tumor specific manner. Here we report that in pediatric malignant soft-tissue tumors, the presence of TAMs and expression of adiponectin (APN) are heterogeneous. Both APN and TAMs had high expression in rhabdomyosarcoma, especially in the malignant subtype, alveolar rhabdomyosarcoma. To investigate the mode of action of APN on TAM activation, a murine MN/MCA1 sarcoma model was used. The Results revealed that exogenous APN had no effect on MN/MCA1 proliferation but tumor size was markedly reduced in apn^-/- mice versus WT controls. The accumulation of TAMs in apn^-/- mice was also reduced which correlated to downregulated serum levels of MCP-1. Likewise, TAMs in apn^-/- mice exhibited a M1-like phenotype, characterized by increase in MHC II^high population and M1 phenotypic markers, such as iNOS gene and serum TNF-α accompanied by a decrease in M2 markers, namely YM1 gene and serum IL-10. In addition, APN deficiency increased the number of CD4⁺ T cells, CD8⁺ T cells and NK cells in tumors and reduced tumor metastasis. The altered phenotype of TAMs in apn^-/- mice was associated with a marked decrease in phospho-p38 and treatment with a p38 MAPK inhibitor significantly reduced tumor size and increased MHC II expression on TAMs in WT mice, implying p38 MAPK signaling pathway may contribute to APN-mediated TAM polarization. Collectively, our findings suggest that APN may have a potential role in regulating soft tissue sarcoma growth. What's New? The localization and function of tumor-associated macrophages (TAMs) in adult tumors are well documented. However, less is known of their presence in pediatric tumors. Here, the authors report for the first time that TAM accumulation is positively associated with adiponectin (APN) expression in infantile rhabdomyosarcoma. Using a murine MN/MCA1 sarcoma model to investigate the mechanisms of this association, they demonstrate that APN deficiency restricts tumor growth, which correlates with a reduction in the number of TAMs. Furthermore, they reveal that APN deficiency allows TAMs to adopt a M1-like phenotype by down-regulating the p38 MAPK signaling pathway.