Antagonizing Integrin beta 3 Increases Immunosuppression in Cancer

Integrin beta 3 activation regulates the balance between antitumor and protumor immune cells through effects on STAT6/STAT1 signaling, probably explaining the generally poor efficacy of integrin antagonists in the clinic and raising questions about their cancer therapeutic utility. Integrin beta 3 is critical for tumor invasion, neoangiogenesis, and inflammation, making it a promising cancer target. However, preclinical and clinical data of integrin beta 3 antagonists have demonstrated no benefit or worse outcomes. We hypothesized that integrin beta 3 could affect tumor immunity and evaluated tumors in mice with deletion of integrin beta 3 in macrophage lineage cells ( beta 3KOM). beta 3KOM mice had increased melanoma and breast cancer growth with increased tumor-promoting M2 macrophages and decreased CD8+ T cells. Integrin beta 3 antagonist, cilengitide, also enhanced tumor growth and increased M2 function. We uncovered a negative feedback loop in M2 myeloid cells, wherein integrin beta 3 signaling favored STAT1 activation, an M1-polarizing signal, and suppressed M2-polarizing STAT6 activation. Finally, disruption of CD8+ T cells, macrophages, or macrophage integrin beta 3 signaling blocked the tumor-promoting effects of integrin beta 3 antagonism. These results suggest that effects of integrin beta 3 therapies on immune cells should be considered to improve outcomes. Cancer Res; 76(12); 3484-95. [copy2016 AACR.