STING signalling as link between DNA damaging therapies and innate immunity in bladder cancer

Background: The immune system can help eliminate cancer cells.

A pre-requisite for successful immunosurveillance and immunotherapy is the presence of a T cell-inflamed “hot” tumour micro-environment, which relies on the secretion of type I interferons and chemokines such as CXCL10 by tumour cells and infiltrating immune cells.

A key signalling cascade that shapes anti-tumour immune functions involves the protein STING (Stimulator of Interferon Genes). STING is activated by the DNA sensor cGAS which detects cytosolic DNA during infection, or following DNA damage.

We have recently discovered that DNA damage can also be detected in the nucleus by the DNA binding proteins IFI16 which leads to the cGAS-independent activation of STIG.

This non-canonical mode of STING activation causes the production of a different, more pro-inflammatory, cytokine and chemokine profile.

We hypothesise that the regulation of STING signalling in cancer cells may be a key factor in the response to DNA damage following radio- or chemotherapy, and has the potential to shape the immune microenvironment and subsequent responses to DNA damaging therapies.

Aims: We will investigate the link between DNA damage, STING activation and innate immune responses to radio- and chemotherapy in bladder cancer.

We aim to (i) find out how DNA damage shapes the innate immune response in normal urothelial cells and cells derived from muscle-invasive bladder cancer, (ii) determine how STING signalling is dysregulated, lost or re-wired in cancer cells, and (iii) generate a multi-parameter model for the personalised prediction of patient responses.

Methods: We will employ mechanistic studies in primary human urothelial cells and cell lines derived from muscle-invasive bladder cancer, and investigate the innate immune response to radio- and chemotherapy using CRISPR gene targeting, cytokine/chemokine profiling and the molecular analysis of signalling complexes.

In vitro findings will be supplemented with the analysis of patient samples by immunohistochemistry, and the mining of transcriptomic and genomic data sets from bladder cancers with associated information on treatment outcomes.

Outcomes: This project will provide mechanistic insights into the regulation of STING signalling in human cancer cells, where STING can have both anti- and pro-tumour functions.

We aim to integrate mechanistic insights with individual tumour data from patients, in order to provide a basis for personalised treatment decisions, based on the innate immune signalling capacity of the tumour.

The project may also lead to the discovery of additional molecular targets for combination therapy approaches in solid tumours.