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Page 2 of 11 Miller et al. J Cancer Metastasis Treat 2019;5:68 I http://dx.doi.org/10.20517/2394-4722.2019.001
[1]
functional impairment” . Cachexia has a negative impact on a large proportion of patients with advanced
[2]
cancer with it contributing to high levels of morbidity and mortality . Although there still remains some
debate over the formal definition of cancer cachexia, it is characterized by unintentional weight loss,
[3]
muscle wasting, anorexia and fatigue . Systemic inflammation is a key driver of cancer cachexia and has
[4,5]
been advocated as a core nutritional assessment in patients with cancer . Pro-inflammatory cytokines
are activated by the tumour mass, and act both centrally (through anorexia) and peripherally (by skeletal
[6]
muscle wasting) to result in host nutritional depletion . Tumour and host-derived factors thus lead to a
[7]
chronic inflammatory and impaired immune state . Immunosuppression is a large problem in cachectic
[8]
cancer patients contributing to reduced responses to surgical and oncological outcomes . The dysfunction
of the immune system is complex and involves multiple mechanisms characterised by a reduction in
monocyte, macrophage, dendritic and natural killer (NK) cell function, ultimately leading to susceptibility
[9]
to infections, and therefore, an overall increase in morbidity .
In short, it has long been apparent that systemic inflammation plays a role in the pathogenesis of cancer
cachexia. The successful therapeutic targeting of systemic inflammation requires a better understanding
of the involved mediators and the link between tumour and immune tissues. This review aims to describe
some of the key elements of immune dysfunction in cachexia and give an overview of previously trialled
immunotherapies.

PRO-CACHECTIC CYTOKINES
TNF-α
[10]
TNF-α (previously known as “cachectin” ) was initially held responsible for causing most of the metabolic
derangements and clinical features of cachexia. TNF-α is released by many types of cell, including
activated macrophages, CD4+, neutrophils, mast cells, eosinophils and neurons. In particular, it can be
produced by tumour, immune and stromal cells to induce growth and survival advantage in the tumour
[11]
microenvironment . Its expression can ultimately lead to anorexia, muscle and adipose wasting, loss of
appetite, increased energy expenditure and insulin resistance in both patients with various types of cancer,
[12]
and the Colon-26 carcinoma mouse model of cancer cachexia (C26) . Many of the effects of TNF-α
arise through activation of NFkB, which in turn leads to activation of the ubiquitin-proteasome pathway
[13]
and skeletal muscle degradation . It also acts to induce oxidative stress and nitric oxide species (NOS).
Experimental evidence suggests TNF-α can induce adipose wasting in white adipose tissue through
inhibition of lipoprotein lipase (LPL), suppression of transcription and promotion of lipolysis [14,15] as well as
stimulation of thermogenesis through increased expression of UCP2 and UCP3 in skeletal muscle.

The role of TNF-α in mediating many of the effects of cancer cachexia was initially supported by evidence
that intraperitoneal injection of soluble recombinant human TNF-receptor antagonist was able to improve
[16]
food intake and thus lead to weight gain in tumour-bearing rats . Lewis lung carcinoma (LLC) mice
deficient in TNF-α receptor protein type 1 showed a reduction in muscle wasting compared with LLC
[17]
wild-type mice despite similar levels of TNF-α being detected in the serum . Treatment with antioxidants
[18]
or NOS inhibitors was shown to increase body weight and prevent muscle wasting in mice . Despite this,
TNF inhibition alone in animals has not been shown to be sufficient to reduce or reverse the cachectic
process indicating that, although it is involved in the pathogenesis of cancer cachexia, it is not solely
[19]
responsible .
Studies in patients with cancer, have also not been successful. In particular adipocytes taken from cancer
[20]
patients, showed no decrease in LPL messenger RNA (mRNA) or LPL enzyme activity . Some studies
have shown raised TNF-α levels in the serum of patients with pancreatic cancer associated with weight loss,
whereas other studies in patients with terminal cancer showed no association between TNF-α and weight
loss [21,22] . Others have shown that TNF-α correlates with stage of disease or tumour size rather than degree