ATR inhibition with radiation creates an inflammatory tumour microenvironment

Dillon, Magnus T.; Bergerhoff, Katharina; Pedersen, Magnus; Whittock, Harriet; Patin, Emmanuel C.; Smith, Helen; Paget, James; Patel, R.; Bozhanova, Galabina; Foo, S.; Campbell, Jessica; Ragulan, Chanthirika; Fontana, Elisa; Wilkins, Anna; Sadanandam, Anguraj; Melcher, Alan; McLaughlin, Martin; Harrington, Kevin

doi:10.1093/annonc/mdy303.019

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“…Further evaluation of AZD6738 in an immunocompetent mouse model of HPV‐driven malignancy also showed that AZD6738 potentiated radiation‐induced inflammatory changes in the tumour microenvironment . An increase in pattern recognition receptors sensing cytoplasmic nucleic acid and ISGs was seen with the addition of ATRi to radiotherapy, compared with radiotherapy alone.…”

Section: Optimising Acute Induction Of Type 1 Ifns In a Therapeutic Cmentioning

confidence: 94%

The immunological consequences of radiation‐induced DNA damage

Wilkins

Patin

Harrington

et al. 2019

The Journal of Pathology

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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.

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Section: Optimising Acute Induction Of Type 1 Ifns In a Therapeutic Cmentioning

confidence: 94%