As solid tumours evolve under immunological pressure, cancer cells are selected for their ability to evade immune attack, either by hiding from or by directly counteracting the immune attack. By subverting mechanisms of immune homeostasis, the tumour microenvironment (TME) can become hostile to anti-tumour immune cells which hampers the effectiveness of therapies such as immune checkpoint blockade (ICB). This has prompted the exploration of combination therapies to reshape the TME to facilitate detection and killing of cancer cells.
Radiotherapy has, in pre-clinical models and in some clinical trials, shown synergy with ICB in improving local tumour control and inducing immune-mediated abscopal effects. However, recent results from clinical trials assessing radiotherapy combinations with ICB have failed to show therapeutic benefit and have dampened the initial optimism. There is an ongoing debate about target lesion selection, radiation target volume, dose, and fractionation, elective nodal irradiation, as well as sequencing of radiotherapy and ICB. These are all important questions for optimizing treatment synergy. However, it is crucial to also determine how these factors impact the tumour microenvironment, the anti-tumour immune response, and the emergence of acquired therapy resistance.
The stimulatory effects of radiotherapy have been well characterised, including upregulation of tumour antigen expression and presentation, induction of immunogenic cell death and activation of viral defence pathways, recruitment and activation of dendritic cells, and ultimately priming of tumour-specific T cell responses. However, the immunosuppressive aspects of radiotherapy in solid tumours (radiation-induced immune checkpoints) are less well understood. These include production of immunosuppressive cytokines, recruitment/polarisation of regulatory immune cells, and upregulation of enzymes that convert pro-immunogenic signals of radiotherapy into immunoregulatory mediators.
The nucleotides ATP and NAD+ are central mediators of cellular metabolism and energy transfer. However, when they are released into the extracellular space from stressed and dying cells, they act as pro-immunogenic danger signals and regulators of tissue homeostasis, primarily via the P2X7 receptor. Radiotherapy promotes the extracellular release of ATP and NAD+ but also modulates the expression of key enzymes that catabolize these molecules resulting in immune resistance. Firstly, radiation induces upregulation of tumour-expressed ectonucleotides, including CD73, which hydrolyse extracellular ATP and NAD+ resulting in accumulation of immunosuppressive adenosine in the tumour microenvironment. Secondly, radiation upregulates tumour expression of the mono-ADP-ribosyltransferase ART1, which utilizes free NAD+ to mono-ADP-ribosylate the P2X7 receptor on CD8 T cells and DCs triggering their elimination by NAD-induced cell death. Our recent work has shown that targeting CD73 and ART1 with therapeutic antibodies, reversed radiation-induced immune resistance promoting tumour infiltration of DCs and augmented CD8 T cell responses in mouse models of lung and mammary carcinoma.
In summary, improved understanding of the balance between immunogenic and suppressive effects of radiotherapy will allow for identification of biomarkers of response and novel targets that can offset radiation-induced immune checkpoints. This will inform the design of rational clinical trials of radiotherapy/immunotherapy combinations which will ultimately help patients with advanced cancer.