Table 2.

Immune barriers and interventions in HPV associated cancer.

Immune event	Negative immune factors	Therapeutic Options
Antigen Release	Inherently stealthy pre-cancer stage of persistent infection provides for facilitating immune deviation including through reduced APC numbers	Selective chemo-, radio- and/or targeted therapies might alter the balance of local factors to boost natural immunity and could help early lesion resolution.
Antigen Presentation	Defective activity of APC & macrophages; accumulation of Tregs, MDSC & establishment of immune deviation in TME.	Any effective therapeutic vaccine against E6/E7 viral oncogenes aims to generate specific killer T cell activity either by boosting natural and/or stimulating new populations. Combination treatments which counter the negative local TME affects by promoting APC activity and the activation of fully functional T cell effectors include provision cytokines like IL-12 cytokines and/or TLR agonists may be useful.
Immune Activation/Priming	Deficiency in macrophages & APC function; sub-optimal stimulation of T cells; unhelpful cytokine skew; inhibitory immune checkpoint expression.	Chronic virus infection positively reinforces the immunosuppressive intensity of the TME. This can ultimately deplete the repertoire although stem-like CD8 cells can preserve this capacity. By this point, checkpoint inhibitors may provide a means to alter the balance of immune factors in favour of regaining control but where additional treatments such as low dose IL-2, or agonists like anti-CD40 might give synergy.
Immune Trafficking	Dysregulation of chemokine and chemokine expression & IFN signalling pathways	Advanced cancer TME may be particularly resilient to immune attacks based on stimulating existing or de novo T cell responses particularly as the latter may not get the guidance signals for tumour homing. ACT of expanded TILS may circumvent some such barriers quantitatively and for homing. Such TIL expanded effectors may also target wider tumour immunogenic genetic changes. CAR T cells might provide sufficiency in effector numbers but target selection is more problematic.
Immune Infiltration	TME driven changes influencing cancer angiogenesis, adhesion, and extravasation plus immune cell apoptosis and activation of the stroma to reduce immune cell infiltration.	The complexity and breadth of TME effects on immune control could be influenced by anti-angiogenesis treatments. Local treatment with immune response modulators (cytokines, TLR agonists) could be helpful but does not address metastatic cancers.
Immune recognition & killing	Evasion of T cell (NK) killing; Upregulation of inhibitory signals like PD-1, PD-L1, LAG-3, TIM etc; consolidation of actively immunosuppressive TME through combination of cellular (Tregs, M2 macrophages, MDSC) and soluble factors (TGFB, IDO, IL-10, etc)	In end stage cancers, the maximal number and extent of TME immunosuppressive influences may require extensive use of combinations of treatments influencing several immune checkpoints, cellular, secreted and metabolic inhibitory factors. The key challenge is to deploy these options including in context of SOC in the best array but also with the optimal sequencing.