Integrin beta3 and immune suppression in cancer

Integrin beta3 is critical for tumor invasion, neoangiogenesis, and inflammation making it a promising cancer target. However, preclinical and clinical data of integrin beta3 antagonists have demonstrated no benefit or worse outcomes. We hypothesized that integrin beta3 could affect tumor immunity and evaluated tumors in mice with deletion of integrin beta3 in macrophage lineage cells (β3KOM). β3KOM mice had increased melanoma and breast cancer growth with increased tumor-promoting M2 macrophages and decreased CD8+ T-cells. Integrin beta3 antagonist, cilengitide, also enhanced tumor growth and increased M2 function. We uncovered a negative feedback loop in M2 myeloid cells wherein integrin beta3 signaling favored STAT1 activation, an M1 polarizing signal, and suppressed M2 polarizing STAT6 activation. Finally, disruption of CD8+ T-cells, macrophages, or macrophage integrin beta3 signaling blocked the tumor-promoting effects of integrin beta3 antagonism. These results suggest that effects of integrin beta3 therapies on immune cells should be considered to improve outcomes.

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