M2 polarization of tumor-associated macrophages is dependent on Integrin β3 via PPARγ up-regulation in breast cancer.

Macrophages are particularly abundant and play an important role throughout the tumor progression process, namely, tumor-associated macrophages (TAM) in the tumor microenvironment. TAM can be polarized to disparate functional phenotypes, the M1 and M2 macrophages. M1-like type macrophages are defined as pro-inflammatory cells involved in killing cancer cells, while M2-like type cells can specially promote tumor growth and metastasis, tissue remodeling and immunosuppression. In this study, we first found that integrin beta 3 was highly expressed on the surface of TAM, both in vivo and in vitro, that displayed the M2-like characteristics. Under intervention of CYC or triptolide, the integrin beta 3 inhibitors, the M2 polarization of TAM could be inhibited. Moreover, in the cell model of M2 polarization, either blockade or knockout/knockdown of integrin beta 3 could also suppress macrophage M2 polarization, which suggested that the M2 polarization was dependent on integrin beta 3. Using knockdown of peroxisome proliferator-activated receptor-gamma (PPAR gamma), an M2 regulator, we found that expression and activation of PPAR gamma participated in M2 polarization that was mediated by integrin beta 3. Finally, to verify the activity of integrin beta 3 inhibitors on TAM in vivo, 4T1 tumor-bearing mice were treated with CYC or triptolide; in response, the M1/M2 ratio of TAM was up-regulated, while the infiltration of total lymphocytes into tumor tissue was not altered. In general, our study found a connection between integrin beta 3 and macrophage polarization, which provides a strategy for facilitating M2 to M1 repolarization and reconstructing the tumor immune microenvironment.