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Cell Metab. 2016 Nov 8;24(5):672-684. doi: 10.1016/j.cmet.2016.10.010.

Tumor-Induced IL-6 Reprograms Host Metabolism to Suppress Anti-tumor Immunity.

Author information

1
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK. Electronic address: tf261@cam.ac.uk.
2
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK; Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. Electronic address: tj212@cam.ac.uk.
3
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK; Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
4
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
5
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
6
University of Cambridge Metabolic Research Laboratories, MRC Metabolic Diseases Unit, Level 4, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
7
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Weill Cornell Medical College, New York, NY 10021, USA.

Abstract

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.

KEYWORDS:

PPARalpha; cachexia; cancer immunology; cancer immunotherapy; glucocorticoids; hepatic metabolism; interleukin-6; ketogenesis; pancreatic cancer; stress

PMID:
27829137
PMCID:
PMC5106372
DOI:
10.1016/j.cmet.2016.10.010
[Indexed for MEDLINE]
Free PMC Article

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