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Miller et al. J Cancer Metastasis Treat 2019;5:68 I http://dx.doi.org/10.20517/2394-4722.2019.001 Page 5 of 11
[50]
through their ability to induce systemic inflammation . Tumours can grow through myelopoiesis and
[51]
the successful evasion of tumour cells from both the innate and adaptive immune systems . However,
the progression of cancers appears dependent on tumour-associated myeloid cells through their ability
[52]
to promote angiogenesis and tissue remodelling . This apparent immunosuppression has been linked to
the development of cachexia in very few studies, despite tumour-induced immunosuppression being well
[53]
documented in the literature .
Myeloid derived suppressor cells (MDSC) may play a role in tumour-related immunosuppression. Tumour-
induced amplification of the myeloid compartment leads to the expansion of myeloid-derived suppressor
cells. MDSC’s are immature myeloid cells in various stages of differentiation, but are not fully differentiated
neutrophils, monocytes/macrophages or dendritic cells. They are found in the bone marrow, spleen, lymph
[50]
nodes and tumours . Their mechanisms of action are not fully understood but they are thought to be
immunosuppressive and to play a role in the over production of cytokines and inflammatory mediators,
which may contribute to cachexia.

MDSC expansion in 4T1 breast carcinoma-bearing mice is associated with the induction of the hepatic
[53]
acute phase protein response and altered fat metabolism . This response is also seen in the C26 and LLC
mouse models. The pro-cachectic acute phase response is not seen, however, in 66C4 subclone of 4TI mice
[53]
in which MDSC expansion does not occur . Defects in myeloid cell-mediated inflammation has also been
shown to result in reduced expression of pro-inflammatory cytokines in the serum of mice with hepato-
[54]
cellular carcinoma . Interestingly, this led to enhanced loss of adipose tissue and decreased macrophage
number in visceral adipose tissue, suggesting a possible local role for macrophages in the regulation
[54]
of cancer-induced fat loss . These findings imply that myeloid cell-mediated inflammation confers a
beneficial function in these rodents, and may provide a potential explanation for the failure of several anti-
inflammatory drugs in treating cachexia. Although a direct link between the development of cachexia and
MDSC’s has not been proven, the above studies have suggested that the development of cancer cachexia is
partly explained by the expansion of immature myeloid populations associated with the tumour.

TAMs
[55]
TAMs increase tumour progression and metastasis and suppress anti-tumour immune functions .
Monocytes from blood infiltrate the tumour and are primed by the tumour microenvironment to exert
[55]
these effects . The immune cells within the tumour’s microenvironment consist of myeloid-derived
[56]
suppressor cells, NK cells, dendritic cells, T cells and macrophages . It is this infiltrate that contributes
to tumour growth and the release of cytokines that promote the pro-cachectic environment. TAMs
are recruited via cytokines and chemokines and suppress the activity of cytotoxic T-lymphocytes via
[57]
programmed cell death 1 ligand 1 (PD-L1) or B7-H4 and other receptors . Activated macrophages also
secrete cytokines leading to the activation of several complex cascades, thereby increasing inflammatory
[58]
status . The chemokine monocyte chemotactic protein-1 is possibly responsible for the migration of
[59]
monocytes to adipose tissue in chronic inflammation . The mechanisms by which macrophages modulate
adipocyte function in cachexia are still unclear.

TILs
TILs are often found in tumours and are thought to reflect an immune response against the tumour.
Many studies report a survival benefit associated with the presence of TIL, suggesting they may delay
tumour progression. CD3+ and CD8+ TILs in particular have been identified as having a positive effect on
[60]
prognosis .

IMMUNE SYSTEM BIOMARKERS
The Neutrophil: Lymphocyte ratio is a prognostic indicator in cancer. Neutrophils increase the
inflammatory reaction to pathogens but also interact with cancer cells to produce cytokines and effector