Trends in Molecular Medicine
Review
Special Issue: Cancer and the Organism
Connecting the Metabolic and Immune Responses to Cancer
Section snippets
Cancer Is a Systemic Disease
Historically, cancer has been considered to be a consequence of systemic pathology. At his time, the physician Claudius Galen (AD 129–200) documented the consensus that cancers arose from over-abundance of a particular bodily fluid, which he designated as ‘black bile’ [1]. This theory remained largely unchallenged until the mid-19th century, when cancer became understood not as an aberration of its host’s fluid composition, but as a consequence of acquired cellular abnormalities 2, 3, 4.
Caloric Deficiency: The Primary Defect of Cachexia
Cachexia, by international consensus, is a clinical syndrome that is defined principally by weight loss (Box 1), and is ‘characterized by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism’ [25]. Reduced food intake is frequently reported in patients with cancer [31], and is considered to be a key underlying mechanism of cachexia, as well as a risk factor for progression from the precachectic to the cachectic state [25]. Reduced
T-Cell Infiltration: The Critical Event in Immune Control of Cancer
A similar point of mechanistic convergence can be sought for the determinants of antitumor immune control. For the adaptive immune system to generate an effective antitumor response, a number of requirements must be met. Cancer cells must express either nonmutated self-antigen or mutated neoantigens that can be recognized by the host repertoire of cytotoxic CD8+ T-cell receptors once they are processed and presented on major histocompatibility complex (MHC) Class I molecules [18].
Connecting Caloric Deficiency and T-Cell Infiltration in Cancer
The observations of cachexia may be accounted for by a normal response to caloric deficiency that is compounded by aberrant processing of metabolic substrates, whilst failures of immune control under checkpoint blockade are robustly associated with relative failure of T-cell infiltration. Through a mechanistic dissection of host metabolism in cachexia, our work in mice has uncovered a tumor-induced systemic immune suppression that causes loss of effector T-cell infiltration, and abolishes
Unresolved Mechanistic Questions of Host Modulation in Cancer
The discovery of endogenous glucocorticoids as a candidate continuous variable that determines the balance between wasting and immunological control of cancer, and of the factors that promote their biosynthesis, raises a number of further mechanistic questions that require evaluation. The mechanism underlying the spontaneous reduction in food intake in cachexia is a priority for future research. Reduced food intake is prevalent in patients with cancer, and reduced food intake in precachectic
Host-Targeted Biomarkers and Therapeutics in Cancer Immunotherapy
The dependence of preclinical immune therapies on circulating glucocorticoids provides a road map toward the development of novel mechanism-based biomarkers and therapeutics (Figure 2, Key Figure). The systemic determinants of glucocorticoid release present candidate biomarkers for patient stratification in immunotherapy. As guided by our own preclinical work, we would suggest that these candidate biomarkers include measurements of food intake, energy expenditure, IL-6 levels, ketone levels,
Concluding Remarks
Recent trends in cancer research include expansion of focus beyond the microcosm of the cancer cell, increased recognition of the response to caloric deficiency in cachexia as a determinant of cancer outcome, and a convergence on T-cell infiltration as a requirement for response to immunotherapies. Systemic glucocorticoids represent a confluence of these trends, as they are induced by the response of precachectic mice to caloric deficiency, and act to suppress both T-cell infiltration and
Acknowledgments
We thank the University of Cambridge, Cancer Research UK, Hutchison Whampoa Limited, the Lustgarten Foundation for Pancreatic Cancer Research, the Ludwig Institute for Cancer Research, the NIHR Biomedical Research Centre, and the Cambridge ECMC. T.R.F. was supported by the Cambridge School of Clinical Medicine’s MB/PhD Programme, T.J. was supported by the Wellcome Trust Translational Medicine and Therapeutics Programme and the University of Cambridge Department of Oncology (RJAG/076). D.T.F. is
Glossary
- Adipose triglyceride lipase
- catalyzes the first step in triglyceride breakdown, converting one triacylglycerol to one diacylglycerol plus a fatty acid.
- Autochthonous tumor
- arises in the location where it subsequently grows and develops. Includes spontaneous, carcinogen-induced and genetically engineered tumors, but not transplantable or injected tumors.
- Cachexia
- syndrome of involuntary weight loss involving depletion of both muscle and fat tissue. It is common in patients with cancer, where it is
References (134)
- et al.
Hallmarks of cancer: the next generation
Cell
(2011) Prognostic effect of weight loss prior to chemotherapy in cancer patients
Am. J. Med.
(1980)Cancer cachexia: mediators, signaling, and metabolic pathways
Cell Metab.
(2012)Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival
Cell
(2010)Definition and classification of cancer cachexia: an international consensus
Lancet Oncol.
(2011)Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials
Lancet Oncol.
(2016)Tumor-induced IL-6 reprograms host metabolism to suppress anti-tumor immunity
Cell Metab.
(2016)- et al.
Treatment of cachexia: an overview of recent developments
J. Am. Med. Dir. Assoc.
(2014) Skeletal muscle UCP2 and UCP3 gene expression in a rat cancer cachexia model
FEBS Lett.
(1998)Weight loss and elevated gluconeogenesis from alanine in lung cancer patients
Am. J. Clin. Nutr.
(2000)
IKKβ/NF-κB activation causes severe muscle wasting in mice
Cell
Muscle wasting in fasting requires activation of NF-κB and inhibition of AKT/mTOR by the protein acetylase, GCN5
J. Biol. Chem.
Stat3 activation links a C/EBPδ to myostatin pathway to stimulate loss of muscle mass
Cell Metab.
Desnutrin, an adipocyte gene encoding a novel patatin domain-containing protein, is induced by fasting and glucocorticoids: ectopic expression of desnutrin increases triglyceride hydrolysis
J. Biol. Chem.
A switch from white to brown fat increases energy expenditure in cancer-associated cachexia
Cell Metab.
Caloric restriction leads to browning of white adipose tissue through Type 2 immune signaling
Cell Metab.
The browning of white adipose tissue: some burning issues
Cell Metab.
PTH/PTHrP receptor mediates cachexia in models of kidney failure and cancer
Cell Metab.
Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity
Cancer Cell
Oncogenic kras-induced GM-CSF production promotes the development of pancreatic neoplasia
Cancer Cell
Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells
Cancer Cell
Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity
Cell
Association between CD8+ T-cell infiltration and breast cancer survival in 12 439 patients
Ann. Oncol.
CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma
Cancer Cell
Facilitating T cell infiltration in tumor microenvironment overcomes resistance to PD-L1 blockade
Cancer Cell
Galen on Food and Diet
A note from history: landmarks in history of cancer, part 1
Cancer
The Emperor of All Maladies: A Biography of Cancer
Cellular Pathology As Based upon Physiological and Pathological Histology
Timeline: chemotherapy and the war on cancer
Nat. Rev. Cancer
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non–small-cell lung cancer to gefitinib
N. Engl. J. Med.
Improved survival with vemurafenib in melanoma with BRAF V600E mutation
N. Engl. J. Med.
Intratumor heterogeneity and branched evolution revealed by multiregion sequencing
N. Engl. J. Med.
Intra- and inter-tumor heterogeneity in a vemurafenib-resistant melanoma patient and derived xenografts
EMBO Mol. Med.
EGFR mutation and resistance of non-small-cell lung cancer to gefitinib
N. Engl. J. Med.
Cancer: antitumour immunity gets a boost
Nature
The blockade of immune checkpoints in cancer immunotherapy
Nat. Rev. Cancer
MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer
Nature
Safety and activity of anti–PD-L1 antibody in patients with advanced cancer
N. Engl. J. Med.
Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients
Nature
Safety, activity, and immune correlates of anti–PD-1 antibody in cancer
N. Engl. J. Med.
Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer
Science
Neoantigens in cancer immunotherapy
Science
PD-1 blockade in tumors with mismatch-repair deficiency
N. Engl. J. Med.
Mechanisms of cancer cachexia
Physiol. Rev.
Mechanisms of metabolic dysfunction in cancer-associated cachexia
Genes Dev.
Cancer cachexia: understanding the molecular basis
Nat. Rev. Cancer
Nutrition and infection
Annu. Rev. Nutr.
Activation of thermogenesis in brown adipose tissue and dysregulated lipid metabolism associated with cancer cachexia in mice
Cancer Res.
Adipose triglyceride lipase contributes to cancer-associated cachexia
Science
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Cancer-Mediated Muscle Cachexia: Etiology and Clinical Management
2021, Trends in Endocrinology and MetabolismCitation Excerpt :IL-6 in particular has long been known as a primary mediator of muscle cachexia, suppressing protein synthesis in skeletal muscle and promoting increased energy expenditure and decreased fat mass [1,23]. It is also known to affect ketogenesis (see Glossary) in the liver by inhibiting peroxisome proliferator-activated receptor-alpha (PPAR-α; reviewed later) [24]. Another member of the IL-6 family, LIF, also induces skeletal muscle wasting and increases lipolysis via receptors on both adipocytes and the hypothalamus [25,26].
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