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Ashdown. J Cancer Metastasis Treat 2022;8:6 https://dx.doi.org/10.20517/2394-4722.2022.01 Page 5 of 9

and antigen as a “prime mover” in the immune response. Moreover, this immune balance is mediated by an
IL-2 centric feedback loop. Importantly, plasticity exists at the cytokine level between these two states [42,43] . A
concept allergists are familiar with is the introduction of low dose antigens to promote tolerance to an
otherwise vigorous response. There exist parallels with tumourigenesis, as presumably, cancer would start
with a single cell with certain mutations and then proliferate, initiating a low tolerising dose of tumour-
[44]
associated antigens (TAAs) . The discontinuity theory of immunity, as articulated by Pradeu and
Vivier , Pradeu and Cooper , and Matzinger’s earlier danger signal hypothesis, provides a supporting
[46]
[45]
[40]
theoretical framework to the experimental observations of Gratz et al. and Pinheiro et al. . Together, this
[41]
helps contextualise the influence of complex, slow, low-dose continuous TAA recognition and how sudden
(perhaps therapy-induced) changes in antigen levels within the TME may subvert immune suppression and
break tolerance in certain circumstances.
Further, interesting parallels in human pregnancy and cancer have also been drawn between the early
immune response and subsequent induction of immune tolerance.

A number of studies have demonstrated that tumour and placenta tissue use the same mechanisms to
[47]
suppress host immunity . The immune privilege offered to develop neoplasms by Tregs mirrors that of a
developing embryo, representing a highly effective and evolutionarily conserved immune tolerance
mechanism that is co-opted by tumours. In midtrimester pregnancy and advanced cancer, systemic
alterations in immunity are also detectable, particularly with respect to a helper T cell type 2 polarisation,
NK induction of tolerogenic/angiogenic dendritic cells and NK permissiveness, despite low levels of major
[48]
histocompatibility complex I expression .
Another reproductive analogy in the context of cytokine cancer therapy is the introduction of the
contraceptive pill. The “pill” came about as a result of detailed research and understanding of the menstrual
cycle’s orchestrated temporal dynamic interaction of reproductive hormones, their levels, cellular receptors
and the various cell types in the female reproductive organ systems. Essentially, the effect of the pill (in part)
was to “trick” the female physiology into thinking she was pregnant. This “trickery” was achieved by
exogenously adding a little bit more of the same hormones (albeit now synthetic) into the system. This
hormonal addition changed the “normal” sequence of events, modulated the reproductive homeostasis and
allowed predictable and successful control of this dynamic system .
[49]

Tricking the system-disturbing immune homeostasis in the TME and breaking tolerance
Numerous mouse models and some translational approaches have shown that tumour immune suppression
following immune recognition is a significant obstacle to breaking immune tolerance . Importantly and as
[50]
argued above, this suppression/tolerance induction is an intentional antigen-specific process mediated by
normal aspects of immune homeostasis and not that dissimilar to pregnancy? Consequently, taking
advantage of our “new” understanding of immune homeostasis and its role in tumour establishment,
maintenance, and progression, reveals promising therapeutic opportunities. Some of which are already
available, and may require minor protocol modifications in order to substantially improve efficacy. From
the immune modulation experience of the past 30 years, it has become apparent that there are several
positions in the tumour immune circuitry that provide opportunities for selective therapeutic intervention
points. These include: Treg ablation with chemo and radiotherapy, bolus cytokine therapy, checkpoint
inhibitor monoclonal antibodies, intratumoural agents, or antigen load modification with various
modalities [50-53] . The latter is discussed below.