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., Fearon, D. T. (November 2016) Tumor-Induced IL-6 Reprograms Host Metabolism to Suppress Anti-tumor Immunity. Cell Metab, 24 (5). pp. 672-684. ISSN 1932-7420 (Electronic)1550-4131 (Linking)

URL: https://www.ncbi.nlm.nih.gov/pubmed/27829137
DOI: 10.1016/j.cmet.2016.10.010

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: Paper
Uncontrolled Keywords: PPARalpha cachexia cancer immunology cancer immunotherapy glucocorticoids hepatic metabolism interleukin-6 ketogenesis pancreatic cancer stress
Subjects: diseases & disorders > cancer
diseases & disorders > cancer > drugs and therapies
CSHL Authors:
Communities: CSHL Cancer Center Program > Signal Transduction
CSHL labs > Fearon lab
CSHL labs > Janowitz lab
Highlight: Janowitz, Tobias
Depositing User: Matt Covey
Date: 8 November 2016
Date Deposited: 14 Nov 2016 22:02
Last Modified: 12 Oct 2018 19:41
PMCID: PMC5106372
Related URLs:
URI: http://repository.cshl.edu/id/eprint/33885

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