Tumor-Induced IL-6 Reprograms Host Metabolism to Suppress Anti-tumor Immunity
Open accessAbstract
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.
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In vivo models of cancer suggest that even low doses of GCs can impair the efficacy of checkpoint immunotherapy and suppress anti-tumor immunity, leading to enhanced metastasis and reduced survival.
“However, in vivo models of cancer also suggests that even low doses of GCs can impair the efficacy of CPI29,30 and suppress anti-tumor immunity,30 leading to enhanced metastasis and reduced survival.31”
From Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy (2023) · cites this paper as [30]
The murine colon-26 (C26) model of cancer progression is characterized by marked elevations in endogenous GC production during disease progression.
“The murine colon-26 (C26) model of cancer progression is characterized by marked elevations in endogenous GC production during disease progression.30”
From Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy (2023) · cites this paper as [30]
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- Authors
- Flint, T. R., Janowitz, T., Connell, C. M., Roberts, E. W., Denton, A. E., Coll, A. P., Jodrell, D. I., & Fearon, D. T.
- Affiliations
- University of Cambridge (GB)
- University of California, San Francisco (US)
- Cornell University (US)
- Corresponding author
- Flint, Thomas R.
- Janowitz, Tobias
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-11
- Volume
- 24
- Issue
- 5
- Pages
- 672-684
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5106372
- OpenAlex
- W2553667461
- Cited by
- 367
- References
- 50
- Citations by year
- 2026: 27 · 2025: 41 · 2024: 34 · 2023: 49 · 2022: 45 · 2021: 56 · 2020: 48 · 2019: 14 · 2018: 32 · 2017: 19 · 2016: 2
- FWCI
- 13.55
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Cell Metabolism (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- University of Cambridge Department of Oncology (RJAG/076)
- Medical Research Council (MRC_MC_UU_12012/1)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Physiology › Dietary Effects on Health
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- host metabolism, energy deficiency, cachexia, PPARα, hepatic ketogenesis, glucocorticoids, corticosterone, pancreatic ductal adenocarcinoma, colorectal cancer, metabolic stress response
- MeSH terms
- Adenocarcinoma, Animals, Cachexia, Glucocorticoids, Immunity, Immunotherapy, Ketosis, Liver, Male, Mice, Inbred BALB C, Neutralization Tests, Pancreatic Neoplasms, Stress, Physiological, Interleukin-6, Caloric Restriction, Cellular Reprogramming
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