TY - JOUR
T1 - Cyclooxygenase-2 inhibition potentiates the efficacy of vascular endothelial growth factor blockade and promotes an immune stimulatory microenvironment in preclinical models of pancreatic cancer
AU - Zhang, Yuqing
AU - Kirane, Amanda
AU - Huang, Huocong
AU - Sorrelle, Noah B.
AU - Burrows, Francis J.
AU - Dellinger, Michael T.
AU - Brekken, Rolf A.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - Resistance to standard therapy remains a major challenge in the treatment of pancreatic ductal adenocarcinoma (PDA). Although anti-VEGF therapy delays PDA progression, therapy-induced hypoxia results in a less differentiated mesenchymal-like tumor cell phenotype, which reinforces the need for effective companion therapies. COX-2 inhibition has been shown to promote tumor cell differentiation and improve standard therapy response in PDA. Here, we evaluate the efficacy of COX-2 inhibition and VEGF blockade in preclinical models of PDA. In vivo, the combination therapy was more effective in limiting tumor growth and metastasis than single-agent therapy. Combination therapy also reversed anti-VEGF-induced epithelial-mesenchymal transition and collagen deposition and altered the immune landscape by increasing tumor-associatedCD8+ T cells while reducing FoxP3+ T cells and FasL expression on the tumor endothelium. Implications: Together, these findings demonstrate that COX-2 inhibition enhances the efficacy of anti-VEGF therapy by reducing hypoxia-induced epithelial plasticity and promoting an immune landscape that might facilitate immune activation.
AB - Resistance to standard therapy remains a major challenge in the treatment of pancreatic ductal adenocarcinoma (PDA). Although anti-VEGF therapy delays PDA progression, therapy-induced hypoxia results in a less differentiated mesenchymal-like tumor cell phenotype, which reinforces the need for effective companion therapies. COX-2 inhibition has been shown to promote tumor cell differentiation and improve standard therapy response in PDA. Here, we evaluate the efficacy of COX-2 inhibition and VEGF blockade in preclinical models of PDA. In vivo, the combination therapy was more effective in limiting tumor growth and metastasis than single-agent therapy. Combination therapy also reversed anti-VEGF-induced epithelial-mesenchymal transition and collagen deposition and altered the immune landscape by increasing tumor-associatedCD8+ T cells while reducing FoxP3+ T cells and FasL expression on the tumor endothelium. Implications: Together, these findings demonstrate that COX-2 inhibition enhances the efficacy of anti-VEGF therapy by reducing hypoxia-induced epithelial plasticity and promoting an immune landscape that might facilitate immune activation.
UR - http://www.scopus.com/inward/record.url?scp=85060931996&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85060931996&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-18-0427
DO - 10.1158/1541-7786.MCR-18-0427
M3 - Article
C2 - 30333153
AN - SCOPUS:85060931996
VL - 17
SP - 348
EP - 355
JO - Molecular Cancer Research
JF - Molecular Cancer Research
SN - 1541-7786
IS - 2
ER -