期刊
CELL METABOLISM
卷 24, 期 5, 页码 672-684出版社
CELL PRESS
DOI: 10.1016/j.cmet.2016.10.010
关键词
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资金
- Lustgarten Foundation for Pancreatic Cancer Research
- Ludwig Institute for Cancer Research
- NIHR Biomedical Research Centre
- Cambridge ECMC
- Rosetrees Trust
- Cambridge School of Clinical Medicine's MB/PhD Programme
- Wellcome Trust Translational Medicine and Therapeutics Programme
- University of Cambridge Department of Oncology [RJAG/076]
- Cambridge University Hospitals NHS Foundation Trust
- CRI Irvington Postdoctoral Fellowship Program
- Medical Research Council (MRC) Metabolic Diseases Unit [MRC_MC_UU_12012/1]
- Cancer Research UK [15678] Funding Source: researchfish
- Medical Research Council [MC_UU_12012/5/B, MC_UU_12012/1] Funding Source: researchfish
- National Institute for Health Research [CL-2011-14-007] Funding Source: researchfish
- MRC [MC_UU_12012/1] Funding Source: UKRI
In patients with cancer, the wasting syndrome, cachexia, is associated with caloric deficiency. Here, we describe tumor-induced alterations of the host metabolic response to caloric deficiency that cause intratumoral immune suppression. In pre-cachectic mice with transplanted colorectal cancer or autochthonous pancreatic ductal adenocarcinoma (PDA), we find that IL-6 reduces the hepatic ketogenic potential through suppression of PPARalpha, the transcriptional master regulator of ketogenesis. When these mice are challenged with caloric deficiency, the resulting relative hypoketonemia triggers a marked rise in glucocorticoid levels. Multiple intratumoral immune pathways are suppressed by this hormonal stress response. Moreover, administering corticosterone to elevate plasma corticosterone to a level that is lower than that occurring in cachectic mice abolishes the response of mouse PDA to an immunotherapy that has advanced to clinical trials. Therefore, tumor-induced IL-6 impairs the ketogenic response to reduced caloric intake, resulting in a systemic metabolic stress response that blocks anti-cancer immunotherapy.
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