期刊
CANCER IMMUNOLOGY RESEARCH
卷 4, 期 6, 页码 520-530出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-15-0235
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资金
- NCI NIH HHS [R01 CA157490, R01 CA190394, R01 CA198074, R01 CA151993, K08 CA138918, R01 CA151588, R01 CA130988, P01 CA154303] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007863] Funding Source: Medline
Autophagy promotes tumor progression downstream of oncogenic KRAS, yet also restrains inflammation and dysplasia through mechanisms that remain incompletely characterized. Understanding the basis of this paradox has important implications for the optimal targeting of autophagy in cancer. Using a mouse model of cerulein-induced pancreatitis, we found that loss of autophagy by deletion of Atg5 enhanced activation of the IkB kinase (IKK)-related kinase TBK1 in vivo, associated with increased neutrophil and T-cell infiltration and PD-L1 upregulation. Consistent with this observation, pharmacologic or genetic inhibition of autophagy in pancreatic ductal adenocarcinoma cells, including suppression of the autophagy receptors NDP52 or p62, prolonged TBK1 activation and increased expression of CCL5, IL6, and several other T-cell and neutrophil chemotactic cytokines in vitro. Defective autophagy also promoted PD-L1 upregulation, which is particularly pronounced downstream of IFN gamma signaling and involves JAK pathway activation. Treatment with the TBK1/IKKe/JAK inhibitor CYT387 (also known as momelotinib) not only inhibits autophagy, but also suppresses this feedback inflammation and reduces PD-L1 expression, limiting KRAS-driven pancreatic dysplasia. These findings could contribute to the dual role of autophagy in oncogenesis and have important consequences for its therapeutic targeting. (C) 2016 AACR.
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