Antagonizing Integrin β3 Increases Immunosuppression in Cancer

Xinming Su, Alison K Esser, Sarah R Amend, Jingyu Xiang, Michael H Ross, Gregory C Fox, Takayuki Kobayashi, Veronica Steri, Kirsten Roomp, Francesca Fontana, Michelle A Hurchla, Brett L Knolhoff, Melissa A Meyer, Elizabeth A Morgan, Julia C Tomasson, Joshua S Novack, Wei Zou, Roberta Faccio, Deborah V Novack, Stephen D RobinsonSteven L Teitelbaum, David G DeNardo, Jochen G Schneider, Katherine N Weilbaecher

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Abstract

Integrin β3 is critical for tumor invasion, neoangiogenesis, and inflammation, making it a promising cancer target. However, preclinical and clinical data of integrin β3 antagonists have demonstrated no benefit or worse outcomes. We hypothesized that integrin β3 could affect tumor immunity and evaluated tumors in mice with deletion of integrin β3 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 β3 antagonist, cilengitide, also enhanced tumor growth and increased M2 function. We uncovered a negative feedback loop in M2 myeloid cells, wherein integrin β3 signaling favored STAT1 activation, an M1-polarizing signal, and suppressed M2-polarizing STAT6 activation. Finally, disruption of CD8+ T cells, macrophages, or macrophage integrin β3 signaling blocked the tumor-promoting effects of integrin β3 antagonism. These results suggest that effects of integrin β3 therapies on immune cells should be considered to improve outcomes. Cancer Res; 76(12); 3484–95. ©2016 AACR.
Original languageEnglish
Pages (from-to)3484-3495
Number of pages12
JournalCancer Research
Volume76
Issue number12
Early online date23 May 2016
DOIs
Publication statusPublished - 15 Jun 2016

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