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Page 4 of 11 Miller et al. J Cancer Metastasis Treat 2019;5:68 I http://dx.doi.org/10.20517/2394-4722.2019.001

IL-1b
IL-1b is a proinflammatory cytokine released by macrophages. It regulates the expression of other cytokines
including IL-6 and IL-12. Recently, the loss of p53 in cancer cells from breast cancer mouse models have
been shown to induce the secretion of WNT ligands that stimulate tumour associated macrophages
(TAMs) to produce IL-1b, therefore helping to drive systemic inflammation. Macrophages were prevented
from secreting IL-1b by pharmacological and genetic blockade of WNT secretion in p53 null cancer cells.
[40]
This blockade also resulted in decreased neutrophilic inflammation and metastasis formation . These
findings therefore suggest an important potential future role for personalised immune therapy in patients
with cancer cachexia.

IL-1b has also been better associated with the clinical features of cachexia such as anorexia, weight loss and
[41]
sarcopenia than other cytokines such as IL-6 in a study of 83 advanced cancer patients . Patients with
gastric cancer cachexia have also been shown to have a higher prevalence of IL-1B+3954 T allele than those
[42]
without indicating that patient genotype plays a role on immunological regulation of cancer cachexia .

IL-6
IL-6 can target adipose tissue, skeletal muscle, gut, and liver tissue, which can all affect cachectic patient
body composition. It signals through the membrane bound receptor gp130 found in most tissues in
[43]
the body . Once bound to its receptor, it activates JAK tyrosine kinase leading to phosphorylation of
tyrosines and the binding of STAT proteins. STAT proteins can translocate to the nucleus and increase the
[43]
transcription of genes involved in immune function, cell proliferation, differentiation and apoptosis .

Several mouse cancer models have clearly demonstrated that blocking IL-6 and associated signalling
can attenuate cachexia progression. Deletion of the IL-6 gene in the APCMin/+ mouse prevented the
[44]
development of cachexia . IL-6 when secreted by tumour cells can also increase autophagy in myotubes
[45]
when joined with soluble IL-6 receptor . IL-6 trans-signalling through the soluble IL-6R has the potential
to amplify IL-6 signalling in the cachectic patient and has been shown to be involved in cross-talk between
[46]
tumour, muscle and adipose tissue in genetic mouse models of pancreatic cancer cachexia . Autophagy
and increasing IL-6 levels have been associated with poor prognosis and weight loss in lung cancer
[45]
patients . It has also been shown to be the key cytokine that regulates the hepatic acute phase response in
[47]
patients with pancreatic cancer cachexia . IL-6 remains a promising therapeutic target in cancer cachexia
but a better understanding of its direct and indirect effects, as well as tissue specific actions, is required.

CYTOKINE GENOTYPE
The presence and concentration of (potentially) pro-cachectic cytokines in cancer patients appear to be
dependent not only on the type of tumour, but also on the burden of disease present, and patient specific
factors such as age, sex and genotype. It is still not fully understood why patients with the same histological
disease may vary with regards to the presence and severity of cachexia. Genetic variation in immunity is
one possible reason. Specific single nucleotide polymorphisms in the IL-1, IL-6 and IL-10 genes have been
[48]
associated with cachexia in gastrointestinal cancers . The 1082G allele in the IL-10 promoter was validated
in an independent cohort. This was shown to be more prevalent in Myc/mTOR-driven mouse models of
[48]
cachexia as well as cachectic colorectal cancer patients . The C allele of the rs6136 polymorphism in the
P-selectin gene has also been associated with weight loss and low CT muscularity in a large group of cancer
[49]
patients . These results suggest a role for the immune system in the complex presentation of cachexia.
CELLS
Myeloid derived suppressor cells
Many studies have now suggested that tumour infiltrating immune cells (those which are mainly of
myeloid origin) are able to differentiate into cells which then promote tumour growth and metastasis