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Page 4 of 9 Ashdown. J Cancer Metastasis Treat 2022;8:6 https://dx.doi.org/10.20517/2394-4722.2022.01

dominant, there is a high degree of plasticity and intermediaries. Macrophage M1/M2 polarisation appears
[27]
to be transient, time and tissue-associated . The M1/M2 phenotypes can shift in response to stimuli in the
TME. As the “vanguard” antigen processor of the host immune response, TAMs offer the possibility to use
their plasticity to modulate the underlying immune suppression, break tolerance and potentially improve
clinical outcomes . MDSCs can inhibit antitumour activities of T and NK cells and stimulate Treg, leading
[28]
to tumour progression through the production of cytokines IL-10 and TGF-β .
[29]
In concert, all these aforementioned diverse immune cell types homeostatically maintain a “tumour-
friendly” microenvironment both locally and systemically under a growing tumour burden. This all points
to an underlying tightly controlled, dynamic “three-way conversation” between tumour cell populations, the
pro-inflammatory and the immunosuppressive immune response circuits. Individually and collectively,
these cells offer opportunities as therapeutic targets.

The positive and negative roles of cytokines within the immune response
Cytokines are produced by a plethora of immune other cells. Both APCs and T and B lymphocytes produce
various cytokines cells in response to antigen processing and recognition. The amount of cytokine produced
is dependent on the amount of antigen encountered and/or its antigenic potential. Interestingly, a number
of specific cytokines play a major role paradoxically in both pro-inflammatory and immunosuppressive
immune cellular pathways, either initiating or homeostatically terminating that immune response. In
addition, another physiological/mechanistic insight is the transient actions of cytokine/receptor cellular
interactions together with normal short half-life restrictions. This temporal aspect contributes to the ability
of cytokines to have selective loco-regional/systemic effects [30-32] .

Three cytokines, in particular, are now appreciated to have opposing duality or bimodal attributes and have
a long history in cancer immunotherapeutics. They are interleukin-2 (IL-2), interferon-γ (IFN-γ) and
tumour necrosis factor-α (TNF-α). Normally, all have relatively short physiologic half-lives [33-35] .

This apparent temporal duality or paradox has confounded their clinical utility of knowing how to
administer these cytokines (with respect to dose and duration) for the best clinical effect. In particular, IL-2
has an extensive 30-year history in treating advanced malignant melanoma (MM) and renal cell carcinoma
RCC. In both incidences, on average, ~7% of patients treated with IL-2 achieve complete responses and
[36]
long-term survival after limited treatment .
Known as the “master cytokine” IL-2, when this agent works successfully, it is clearly modulating an
underlying/pre-existing tumour-specific immune response. The paradox arose in the mid-1990s when it
was discovered that IL-2 also stimulates Tregs and can suppress an immune response . Thus, this provided
[37]
an explanation for its limited and random efficacy. Similar duality opposing activity over Tregs was later
elucidated for IFN-γ and TNF-α [34,35] . More recently, similar attributes have been reported for PD-1 &
CTLA4 monoclonal antibodies (Mabs) as their targets are also expressed on Tregs, and blockade can cause
tumour hyperprogression and self-limit efficacy [38,39] .

Antigen load, recognition and tolerance induction - a critical insight
Improved understanding of the immune system’s role in cancer has reinvigorated research on the interplay
between antigen load and immune tolerance induction. Indeed, elegant work by Gratz et al. and
[40]
Pinheiro et al. has shown that initial low levels of antigen promote Tregs and subsequently control the
[41]
balance between T-effector lymphocytes & Tregs and thus the balance between responsiveness and
tolerance. This is a critically important insight into the fundamental nature of cancer immune suppression