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

Transmutability of antigen to cytokine conversion within and the adjacent TME
Perhaps the simplest approach to immune modulation in order to break tumour tolerance appears to be
using the TME’s (and surrounding tissue’s) own resident APCs to generate endogenous INF dominant
cytokine production . Causing sufficient tumour cell destruction and complex antigen production, at the
[54]
same time preserving the nearby TME’s APCs, has the potential via STING/ DAMP signalling pathways to
[55]
break tumour tolerance locally and systemically . A number of intratumoural strategies do the same thing;
they supply a complex “soup” of antigen as a “burst” to the TME, which then is rapidly converted via APCs
to INFs [56,57] . Modalities such as radiotherapy, high intensity focused ultrasound, radio wave ablation,
cryotherapy, intratumoural food dye rose bengal, diterpene esters, all cause localised tumour cell
destruction for immune processing and TME remodelling [58-61] . Similarly, it is now appreciated that the
principal local and systemic mechanism of action of oncolytic viruses is caused by the lytic induced immune
[62]
response against viral-infected cells .

[64]
[63]
Ground-breaking clinical work by Tubin et al. . and confirmed by Markovsky et al. . in mouse
experiments, demonstrated that systemic immune modulation and complete abscopal responses could be
achieved by single/double dose partial tumour irradiation, particularly incorporating the hypoxic segment
in the radiation field. Partial tumour hypofractionated (1-3 doses) irradiation preserves the TME’s cellular
immune signalling capabilities in the un-irradiated segment to do the “heavy lifting” locally and systemically
via an ensuing antigen/cytokine-induced antitumour immune response [63,64] .

CONCLUSION
Finally, our relatively recent understanding of the immune cellular components and interactions within the
TME and their role in tumourigenesis and maintenance provides evidence on how to better use existing
modalities to improve therapeutic outcomes. Further, these insights explain why earlier crude attempts at
cancer immunotherapy worked occasionally/randomly and really not better than today’s much more
sophisticated varied attempts.

We now know the immune system is homeostatically suppressed, with the immune system tightly
protecting the tumour burden from immune destruction. Normal inflammatory controls by loco-regional
TAMs, Tregs, MDSCs, together with orchestrating cytokines such as IL2, INF-γ and TNF-α involved in
physiologic feedback loops, maintain the tumour friendly TME.

The prime mover in this suppression is the antigen load coming from the tumour. An apparent “normal”
tissue in the eyes of the immune system, the tumour is not that dissimilar to the developing embryo.

We also know that introducing extra therapeutic cytokine into the intratumoural system can destabilise the
status quo and thus interrupt “a natural course of events”. Rather than attempting to immune modulate
systemically and “deep” into the immune circuitry with toxic, expensive and inconsistent drugs, the simplest
emerging and comprehensive solution may be to use therapeutic modalities that utilise the local TME APC
machinery. Complex antigen loading via the STING/PAMPS pathways can induce endogenous cytokine
production at sufficient levels to “throw a spanner in the works” of the underlying homeostatic suppression
and break tolerance locally and systemically.

Further, evidence this can happen with various agents and modalities is appearing in the abscopal/bystander
literature . Clearly, the spatio-temporal influences of tumour-specific antigen load, the resultant cytokine
[65]
production and the presence of opposing cell populations homeostatically balanced, are waiting to be used.
In the face of a growing tumour burden, the system can be easily destabilised and thus break the