Journal
CANCER RESEARCH
Volume 76, Issue 12, Pages 3484-3495Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-15-2663
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Funding
- NIH [RO1-CA097250, PO1-CA100730, RO1-CA154737, 5T32GM007067-39, T32AR060719, 5T32CA113275-07, R01-AR057037, R37-AR046523]
- Shriners Hospitals for Children [85400-STL]
- German Research Society [DFGSCH682/3-1]
- Fonds Nationale de La Recherche de Luxembourg (CORE Itgb3VascIn)
- EU [CIG303682]
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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. (C) 2016 AACR.
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