Tumor-Induced IL-6 Reprograms Host Metabolism to Suppress Anti-tumor Immunity Academic Article uri icon

Overview

MeSH Major

  • Cellular Reprogramming
  • Immunity
  • Interleukin-6
  • Pancreatic Neoplasms

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┬áketogenic 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.┬áMultiple 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.

publication date

  • November 8, 2016

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5106372

Digital Object Identifier (DOI)

  • 10.1016/j.cmet.2016.10.010

PubMed ID

  • 27829137

Additional Document Info

start page

  • 672

end page

  • 684

volume

  • 24

number

  • 5