The immunological consequences of radiation‐induced DNA damage

Abstract

Historically, our understanding of the cytotoxicity of radiation has centred on tumour cell-autonomous mechanisms of cell death. Here, tumour cell death occurs when a threshold number of radiation-induced non-reparable double-stranded DNA breaks is exceeded. However, in recent years, the importance of immune mechanisms of cell death has been increasingly recognised, as well as the impact of radiotherapy on non-malignant cellular components of the tumour microenvironment. Conserved antiviral pathways that detect foreign nucleic acid in the cytosol and drive downstream interferon (IFN) responses via the cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of IFN genes (cGAS/STING) pathway are key components of the immune response to radiation-induced DNA damage. In preclinical models, acute induction of a type 1 IFN response is important for both direct and abscopal tumour responses to radiation. Inhibitors of the DNA damage response show promise in augmenting this inflammatory IFN response. However, a substantial proportion of tumours show chronic IFN signalling prior to radiotherapy, which paradoxically drives immunosuppression. This chronic IFN signalling leads to treatment resistance, and heterotypic interactions between stromal fibroblasts and tumour cells contribute to an aggressive tumour phenotype. The effect of radiotherapy on myeloid cell populations, particularly tumour-associated macrophages, has an additional impact on the immune tumour microenvironment. It is not yet clear how the above preclinical findings translate into a human context. Human tumours show greater intratumoural genomic heterogeneity and more variable levels of chromosomal instability than experimental murine models. High-quality translational studies of immunological changes occurring during radiotherapy that incorporate intrinsic tumour biology will enable a better understanding of the immunological consequences of radiation-induced DNA damage in patients.

Radiation therapy and anti-tumor immunity: exposing immunogenic mutations to the immune system

“…Focal radiotherapy (RT) has been used for more than a century to attain local tumor control. The DNA damage caused by RT mediates its cytocidal effects, but is also responsible for many of the pro-inflammatory effects of RT because DNA that gains access to the cytosol of cancer cells and myeloid cells within the irradiated tumor microenvironment acts as a powerful DAMP [14, 15]. In pre-clinical studies, RT has been demonstrated to induce the activation of T cells that are directed against model antigens introduced into cancer cells, such as ovalbumin, and against some endogenous tumor antigens [16–18].…”

Recent advances in breast cancer research impacting clinical diagnostic practice

“…The ‘abscopal effect’ is a term used to describe the fact that locoregional radiotherapy of breast cancer reduces the risk of distant, as well as local, recurrences. Consistent with this, there is growing evidence from preclinical models that local radiation treatment indirectly enhances systemic anti‐tumour immune activity, possibly as a result of immunogenic molecules being released from dead or dying tumour cells (reviewed in ). It follows then that the sequence of administration of locoregional and systemic therapies, with immune modulators, may be crucial in order to maximise any abscopal effect.…”

More than Meets the ISG15: Emerging Roles in the DNA Damage Response and Beyond

“…By contrast, overexpression of ISG15 can confer gemcitabine resistance in pancreatic cancer cells [161]. Additional studies investigating IFN-driven drug resistance signatures also identify ISG15 as a key marker for resistance to genotoxic therapies involving chemotherapeutic drugs, such as DNA methyltransferase (DNMT) or histone deacetylase (HDAC) inhibitors, or radiotherapy [118,152,[184][185][186][187][188]. While the roles of ISG15 in drug sensitivity are unclear, these studies not only hint at functions for ISG15 in genome stability, but also touch on the possibility of interplay between the innate immune system and the DDR.…”