Tumor-induced IL-6 reprograms host metabolism to suppress anti-tumor immunity

Flint, T. R., Janowitz, T., Connell, C. M., Roberts, E. W. , Denton, A. E., Coll, A. P., Jodrell, D. I. and Fearon, D. T. (2016) Tumor-induced IL-6 reprograms host metabolism to suppress anti-tumor immunity. Cell Metabolism, 24(5), pp. 672-684. (doi: 10.1016/j.cmet.2016.10.010) (PMID:27829137) (PMCID:PMC5106372)

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.

• Item Type: Articles
• Additional Information: This work was also supported by the Lustgarten Foundation for Pancreatic Cancer Research, the Ludwig Institute for Cancer Research, the NIHR Biomedical Research Centre, and the Cambridge ECMC. T.R.F. was supported by the Rosetrees Trust and the Cambridge School of Clinical Medicine’s MB/PhD Programme, T.J. was supported by the Wellcome Trust Translational Medicine and Therapeutics Programme and the University of Cambridge Department of Oncology (RJAG/076), C.M.C. was supported by the Cambridge University Hospitals NHS Foundation Trust, E.W.R. was supported by the CRI Irvington Postdoctoral Fellowship Program, and A.P.C. was supported by the Medical Research Council (MRC) Metabolic Diseases Unit (MRC_MC_UU_12012/1). D.T.F. is a Distinguished Scholar of the Lustgarten Foundation.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Roberts, Dr Ed
• Authors: Flint, T. R., Janowitz, T., Connell, C. M., Roberts, E. W., Denton, A. E., Coll, A. P., Jodrell, D. I., and Fearon, D. T.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell Metabolism
• Publisher: Elsevier (Cell Press)
• ISSN: 1550-4131
• ISSN (Online): 1932-7420
• Copyright Holders: Copyright © 2016 The Authors
• First Published: First published in Cell Metabolism 24(5):672-684
• Publisher Policy: Reproduced under a Creative Commons License