Editors' ChoiceCancer Immunology

Cancer, host metabolism, and immunotherapy

Sci. Signal.  22 Nov 2016:
Vol. 9, Issue 455, pp. ec276
DOI: 10.1126/scisignal.aal4333

Cachexia is a disease characterized by muscle wasting and weight loss and is common in patients with pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC). Patients with PDAC respond poorly to immunotherapy. Tumor secretion of the inflammatory cytokine interleukin-6 (IL-6) is associated with cachexia. Using mouse models and patient samples, Flint and Janowitz et al. found that the failure of immunotherapy in some patients might be caused by the effects of tumor-secreted IL-6 on an intricate axis connecting the liver, the brain, and the immune system. Compared with caloric-restricted control animals without tumors, mice that were cachectic or caloric-restricted and had PDAC or CRC had lower plasma concentrations of glucose and ketones but higher concentrations of the stress hormone corticosterone and the inflammatory cytokine IL-6. Cachectic patients with PDAC also had low plasma ketone and high plasma corticosterone and IL-6. Ketones are produced in the liver through activation of the transcription factor PPAR-γ. Compared with control mice, the abundance of PPAR-γ in the liver was decreased in tumor-bearing mice and further decreased in tumor-bearing mice with cachexia or caloric restriction. Intravenous injection of recombinant IL-6 into control mice or a neutralizing antibody to IL-6 to precachectic tumor-bearing mice indicated that tumor-secreted IL-6 was critical in suppressing hepatic ketogenesis. Transcriptional and histological analyses of tumors from precachectic and cachetic mice revealed that innate and adaptive immune cell infiltration was decreased in cachectic tumors, a phenomenon that was also induced by food restriction in precachectic tumor-bearing mice. Glucocorticoids are used pharmacologically as immune suppressants. Implanting precachectic (freely feeding) tumor-bearing mice with corticosterone-releasing subcutaneous pellets decreased intratumoral T cell infiltration, whereas injecting mice with the glucocorticoid synthesis inhibitor aminoglutethimide inhibited the fasting-induced increase in corticosterone production and improved intratumoral immune infiltration in fasting mice. The growth of PDAC tumors in mice that were implanted with corticosterone-releasing pellets was not affected by various immunotherapies, whereas the growth of tumors in mice implanted with placebo pellets was prevented by immunotherapy. These findings show that tumor-induced changes to liver metabolism trigger stress hormone production and immunosuppression. Targeting this axis—by blocking IL-6 or corticosterone signaling, for example—might enhance immunotherapy in PDAC and CRC patients.

T. R. Flint, T. Janowitz, C. M. Connell, E. W. Roberts, A. E. Denton, A. P. Coll, D. I. Jodrell, D. T. Fearon, Tumor-induced IL-6 reprograms host metabolism to suppress anti-tumor immunity. Cell Metab. 24, 672–684 (2016). [PubMed]

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