Tumor-Induced IL-6 Reprograms Host Metabolism to Suppress Anti-tumor Immunity.
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.
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK. Electronic address: tf261@cam.ac.uk.
Thomas R
TR
Flint
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK; Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK. Electronic address: tj212@cam.ac.uk.
Tobias
T
Janowitz
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK; Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
Claire M
CM
Connell
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
Edward W
EW
Roberts
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
Alice E
AE
Denton
University of Cambridge Metabolic Research Laboratories, MRC Metabolic Diseases Unit, Level 4, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
Anthony P
AP
Coll
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
Duncan I
DI
Jodrell
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Weill Cornell Medical College, New York, NY 10021, USA.
Douglas T
DT
Fearon
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002100:Cachexia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D031204:Caloric Restriction; D065150:Cellular Reprogramming; D005938:Glucocorticoids / Q000378:metabolism; D007109:Immunity; D007167:Immunotherapy; D015850:Interleukin-6 / Q000172:deficiency / Q000378:metabolism*; D007662:Ketosis / Q000150:complications / Q000473:pathology; D008099:Liver / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D013312:Stress, Physiological
D005938:Glucocorticoids; D015850:Interleukin-6
PPARalpha; cachexia; cancer immunology; cancer immunotherapy; glucocorticoids; hepatic metabolism; interleukin-6; ketogenesis; pancreatic cancer; stress