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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Animals
  • Cachexia / immunology
  • Cachexia / metabolism
  • Cachexia / pathology
  • Caloric Restriction
  • Cellular Reprogramming*
  • Glucocorticoids / metabolism
  • Immunity*
  • Immunotherapy
  • Interleukin-6 / deficiency
  • Interleukin-6 / metabolism*
  • Ketosis / complications
  • Ketosis / pathology
  • Liver / metabolism
  • Male
  • Mice, Inbred BALB C
  • Neutralization Tests
  • Pancreatic Neoplasms / immunology*
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Stress, Physiological


  • Glucocorticoids
  • Interleukin-6