M2 polarization of tumor-associated macrophages is dependent on Integrin beta3 via PPARgamma up-regulation in breast cancer.

Macrophage is particularly abundant and plays an important role throughout the tumor progression process, namely, tumor-associated macrophage (TAM) in the tumor microenvironment. TAM can be polarized to disparate functional phenotypes, as M1 and M2 macrophages. The type of M1-like is defined as proinflammatory cells involved in killing cancer cells, while M2-like type can specially promote tumor growth and metastasis, tissue remolding and immunosuppression. In this study, we firstly found that Integrin beta3 was expressed highly on the surface of TAMs both in vivo and in vitro, which displayed the M2-like characteristic properties. Thereupon, under intervention of CYC or triptolide, the Integrin beta3 inhibitors, the M2 polarization of TAMs could be inhibited. Moreover, in the cell model of M2 polarization, either blockade or knockout/down of Integrin beta3 could also suppress macrophages M2 polarization, which suggested that the M2 polarization was dependent on Integrin beta3. Utilizing knockdown of PPARgamma, a M2 regulator, we found that expression and activation of PPARgamma participated in M2 polarization which was mediated by Integrin beta3. Finally, to verify the activity of Integrin beta3 inhibitors on TAM in vivo, the 4T1 tumor-bearing mice were treated with CYC or triptolide, where M1/M2 ratio of TAMs was up-regulated, while the infiltration of total lymphocytes into tumor tissue was not altered at all. In general, our study found the connection between Integrin beta3 and macrophages polarization, which provide a strategy for facilitating M2-to-M1 repolarization and reconstructing tumor immune microenvironment.