Antagonizing Integrin ?3 Increases Immunosuppression in Cancer.

ABSTRACT: Integrin ?3 is critical for tumor invasion, neoangiogenesis, and inflammation, making it a promising cancer target. However, preclinical and clinical data of integrin ?3 antagonists have demonstrated no benefit or worse outcomes. We hypothesized that integrin ?3 could affect tumor immunity and evaluated tumors in mice with deletion of integrin ?3 in macrophage lineage cells (?3KOM). ?3KOM mice had increased melanoma and breast cancer growth with increased tumor-promoting M2 macrophages and decreased CD8(+) T cells. Integrin ?3 antagonist, cilengitide, also enhanced tumor growth and increased M2 function. We uncovered a negative feedback loop in M2 myeloid cells, wherein integrin ?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 ?3 signaling blocked the tumor-promoting effects of integrin ?3 antagonism. These results suggest that effects of integrin ?3 therapies on immune cells should be considered to improve outcomes. Cancer Res; 76(12); 3484-95. ©2016 AACR.

SUBMITTER: Su X 

PROVIDER: S-EPMC4944657 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature