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Ashdown. J Cancer Metastasis Treat 2022;8:6 https://dx.doi.org/10.20517/2394-4722.2022.01 Page 3 of 9

[9]
growing tumour burden and creating substantial multilayered barriers to therapeutic success . Remove or
interfere with the mechanistic components of these immune circuits; these barriers can be broken down and
[10]
can lead to tumour destruction, complete responses and improved survival . Arguably, the most important
critical lesson learnt with respect to the TME induced immune suppression is the realisation that this
suppression has been caused by normal immune homeostasis. This homeostatic impasse is an intentional
part of the way the immune system processes antigens and stops unwanted inflammation and damage to
surrounding “normal” tissue. Importantly and recently, this impasse is being appreciated as being
[11]
reversible . Understanding a few simple rules of this homeostatic process has the potential to remove the
“hit and miss” randomness that currently exists in cancer therapies.

So who is the real enemy here, the cancer or the immune system?
After decades of failure of tumour-centric approaches to cancer therapy, attention has gradually now turned
to our immune system to do the “heavy lifting”.

Irrespective of tumour morphology, patients with advanced cancer exhibit simultaneous immune activation
[12]
and suppression . While the TME consists of both cancerous and non-cancerous cells, most of these
subpopulations cooperate synergistically to drive via positive feedback loops that are conducive to
tumourigenesis. Further, the resultant local inflammatory environment appears to be a consistent
component of malignant tumours and displays increasing concentrations of cytokines locally and
systemically, particularly with rising disease burden . Malignant tumours can significantly interfere with
[13]
the patient’s immune system, leading to fevers, paraneoplastic autoimmunity and sepsis [14,15] . Thus, despite a
general environment of immune stimulation, evidence suggests that anti-tumour immune responses are
being continuously attenuated, and this appears universal across the tumour types [16,17] .

The immune system has evolved the ability to recognise, destroy and remember foreign or corrupted
peptides and antigens that are detrimental to our survival. Estimates suggest that the somatic
hypermutation/recombination mechanisms to generate antigen-specific receptors in T cells can program for
as many as 10 possible unique receptors . This diverse repertoire suggests that a functional immune
[18]
15
system should be able to accommodate cancer adaptability and mutational drift. In support of the
aforementioned, laboratory assays can detect T and B cell responses (autoantibodies etc.) to tumour-
associated antigens and therapy-induced neoantigens [19-21] . Also, assays can detect attenuating antigen-
specific regulatory T cell responses and indicative pro-inflammatory and immune-suppressive
cytokines/inflammatory markers [22,23] .

The immune cells of the TME and their function
The TME can consist of a diverse immune cellular presence, including T and B lymphocytes, natural killer
(NK), natural killer T (NKT) cells and regulatory T cells (Tregs). Tregs comprise diverse subsets of
immunosuppressive cells that play critical roles in not only maintaining immune homeostasis and self-
tolerance, but also suppressing antitumour responses of cytotoxic lymphocytes. Other important cells
include tumour-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCS). All these
cells can account for circa 10% of the total tumour cell population and can also be found in substantial
concentrations within the tumour and in the tumour periphery. Collectively, they are major drivers of an
immunosuppressive TME. TAMs exhibit both anti- and pro-tumoural effects. The high density of TAMs is
a characteristic of most tumours and has been correlated to poor clinical outcomes [24-26] .

Within the TME, TAMs can polarise to M1-like pro-inflammatory interferon-γ phenotype or the anti-
inflammatory/immunosuppressive M2-like phenotype, which induces the secretion of IL-10 and TGF-β to
limit inflammation, enhances tissue repair, and promotes vascularisation. While these two TAMs are