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)
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 CSHL Cancer Center Program > Cellular Communication in Cancer Program |
| Highlight: | Janowitz, Tobias |
| Depositing User: | Matt Covey |
| Date: | 8 November 2016 |
| Date Deposited: | 14 Nov 2016 22:02 |
| Last Modified: | 26 Oct 2020 16:03 |
| PMCID: | PMC5106372 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/33885 |
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