Review
Special Issue: Cancer and the Organism
Connecting the Metabolic and Immune Responses to Cancer

https://doi.org/10.1016/j.molmed.2017.03.001 Get rights and content

Trends

The scope of cancer research is expanding to include the molecular circuitry of both cancer cells and non-cancer cells, as well as non-tumor tissues of the cancer host.

The current generation of immune therapies target cells of the cancer host. These therapies achieve durable remissions of advanced cancers, but the majority of patient subsets remain unresponsive.

Tumors affect their hosts’ metabolism, often leading to the lethal wasting syndrome, cachexia. In recent years, the biology of cachexia has become an increasingly active field of mechanistic research, but still defies a unifying explanation.

Preclinical studies have now connected the host’s metabolic and immune responses to cancer. Tumors reprogram the normal metabolic response to caloric deficiency in cachexia, leading to suppression of the antitumor immune reaction.

Separate research fields have advanced our understanding of, on the one hand, cancer immunology and, on the other hand, cachexia, the fatal tumor-induced wasting syndrome. A link between the host’s immune and metabolic responses to cancer remained unexplored. Emerging work in preclinical models of colorectal and pancreatic cancer has unveiled tumor-induced reprogramming of liver metabolism in cachexia that leads to suppression of antitumor immunity and failure of immunotherapy. As research efforts in metabolism and immunology in cancer are rapidly expanding, it is timely to discuss the metabolic and immunological determinants of the cancer–host interaction. We also present the hypothesis that the convergence of host metabolism and antitumor immunity may offer a platform for biomarker-driven investigations of new combination therapies.

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

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      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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