Page 337 - Read Online

Paul J Cancer Metastasis Treat 2020;6:29 I http://dx.doi.org/10.20517/2394-4722.2020.63 Page 15 of 31

receptor 4 and IL-12 [109] , exosomes can down regulate the functions of immune cells [110,111] , may promote
Tregs expansion [112] , and inhibit the activity of natural killers (NK) cells [113] .

As is the case with inflammation, there is a co-dependent relationship between the immune system and
the gut microbiome. The immune system plays an important role in defining the composition of the
microbiota and preserving the ecology of the microbiota. Reversely, the microbiota influences all aspects
of the immune system. Gut microbiome plays an important role in the training and the functional tuning
of the immune system and can be seen as one of the key modulators of the immune system [114] . In addition
to influencing localized immune responses, microbiota also has broader effects contributing to innate and
adaptive immunity at multiple levels [115] . Myeloid cells respond to microbial signals, and initiate innate
[99]
and adaptive immune responses . In 2013, it has been shown in two murine models that germfree or
antibiotic-treated animals did not respond to chemotherapy, indicating that an intact microbiome was required
for modulating the myeloid-derived immune cell responses in the tumor microenvironment [97,98] . Alterations
in the gut microbiome can affect response to immunotherapy in several cancer types. Matson et al. [116]
identified different bacterial species as being critical for response to therapy in their patients with advanced
melanoma, with Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium, among
others, found to be enriched in the feces of patients that responded to anti-PD-L1. Similar findings were
reported by Routy et al. [117] in patients with advanced urothelial carcinoma, non-small cell lung cancer, and
renal cell carcinoma. Patients who have been treated with antibiotics within several months before, during,
or after treatment with PD-1/PD-L1 blockade had shorter progression-free survival and lower overall
survival rates compared with patients who had not received antibiotics. After sequencing fecal samples
from these patients, the genera Akkermansia and Alistipes were enriched, and, the bacterial species A.
muciniphila, specifically, was found to be highly represented in patients that responded to checkpoint
blockade.

The immune cells play a dual role in cancer [118,119] . Classically, some immune cells may promote cancer
growth (M2 macrophages, T regs cells) and others fight cancer (M1 macrophages, CD8 cells). This is
an over simplification as the same type of cells may play a pro, or anti-neoplastic role depending on
the local and systemic context. For example, in the majority of cancers, an increased number of T regs
in the tumor is associated with a poor prognostic, but in patients with colon or breast carcinomas, the
presence and frequency of T reg in the tumor is correlated with an improved prognostic [120] . A similar
phenomenon has been shown for tumor associated macrophages [121] . Like macrophages and T reg cells,
tumor-associated neutrophils and NK cells may have both antitumoral and protumoral functions [122] .
As shown in by Labelle et al. [123] , platelets attract neutrophils into the tumor thrombi contributing to the
metastatic niche development. Also, a high neutrophil to lymphocyte ratio, predicts poor outcome in
several types of cancer including lung cancer, pancreatic cancer and colorectal cancer. There is new data
showing direct involvement of neutrophils in different types of cancer and there is increasing evidence in
preclinical models that granulocyte-CSF (G-CSF) can promote metastasis [124,125] . Also, as shown by several
research teams, metastatic cancer cells can induce neutrophils to form metastasis-supporting neutrophil
extracellular traps (NETs) and drugs that degrade NETs have been shown to have a profound inhibitory
effect on the development of metastatic disease in preclinical models [126,127] .

The global metabolism/cachexia network
In order to ensure sufficient biomass synthesis for their growth, cancer cells need to maintain high
metabolic turnover rates. A large amount of energy is required to support this process. For example, an
estimated ~17,700 kcal are required over 3 months to support metastatic colorectal cancer growth [128] .
Since the seminal work of Warburg [129] , it has been observed cancer cells have distinct metabolic programs
than normal cells and metabolic reprogramming has been acknowledged as one of the classical hallmarks
[19]
of cancer . The most distinctive metabolic differences of cancer tissues are increased aerobic glycolysis,