TY - JOUR
T1 - Antagonizing integrin β3 increases immunosuppression in cancer
AU - Su, Xinming
AU - Esser, Alison K.
AU - Amend, Sarah R.
AU - Xiang, Jingyu
AU - Xu, Yalin
AU - Ross, Michael H.
AU - Fox, Gregory C.
AU - Kobayashi, Takayuki
AU - Steri, Veronica
AU - Roomp, Kirsten
AU - Fontana, Francesca
AU - Hurchla, Michelle A.
AU - Knolhoff, Brett L.
AU - Meyer, Melissa A.
AU - Morgan, Elizabeth A.
AU - Tomasson, Julia C.
AU - Novack, Joshua S.
AU - Zou, Wei
AU - Faccio, Roberta
AU - Novack, Deborah V.
AU - Robinson, Stephen D.
AU - Teitelbaum, Steven L.
AU - Denardo, David G.
AU - Schneider, Jochen G.
AU - Weilbaecher, Katherine N.
N1 - Publisher Copyright:
©2016 AACR.
PY - 2016/6/15
Y1 - 2016/6/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84976871341&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-15-2663
DO - 10.1158/0008-5472.CAN-15-2663
M3 - Article
C2 - 27216180
AN - SCOPUS:84976871341
SN - 0008-5472
VL - 76
SP - 3484
EP - 3495
JO - Cancer research
JF - Cancer research
IS - 12
ER -