Walker, Thomas and Unterholzner, Leonie (2024) Disparate STING signalling as a link between bladder cancer cell innate immune response and the immunostimulatory state of the tumour microenvironment following genotoxic therapies. In: Cancer Research UK: Cancer and the host - tumour immunology, 2024-05-07 - 2024-05-07, The Francis Crick Institute.
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Abstract
Objectives A T cell-inflamed immunostimulatory tumour microenvironment (TME) is required for successful cancer cell clearance, and for checkpoint inhibitor immunotherapies, whilst a suppressive TME correlates with resistance and poor prognosis. Chemotherapy (CT) or radiotherapy (RT) can direct both immunostimulatory and immunosuppressive states. DNA damage can elicit cytosolic micronuclei which are detected by the DNA sensor cGAS and its adaptor STING. Nuclear DNA damage can also be detected via cGAS-independent STING activity which presents a distinct pro-inflammatory cytokine profile. We are investigating the role of DNA damage-driven innate immune responses in muscle-invasive bladder cancer. Bladder cancer presents with significant recurrence and mortality following standard-of-care cystectomy. Its high mutational load offers a favourable model system to study disparate STING pathway signalling following CT/RT and correlation with the TME immunoreactive state. Methods We are analysing a panel of muscle-invasive bladder cancer cell lines for their mechanistic innate immune responses following treatment with CT agents and IR which mirror UK NICE bladder cancer management guidelines. Micronuclei burden and activation states of cGAS-dependent and cGAS-independent STING signalling were determined through quantitative confocal microscopy, qRT-PCR and ELISA. Results Bladder cancer cells display a range of cytotoxic and cytostatic responses following CT agent treatment. We find that sub-lethal CT doses cause an innate immune response in cancer cells, and that the cells in the panel differ in their ability to activate cGAS-dependent and independent STING signalling and the resulting spectrum of type I interferon and cytokine profiles. Conclusions Bladder cancer cytotoxic and innate immune STING activity states are highly relevant to the mechanistic understanding of responses to CT/RT. Ongoing work will integrate innate immune signatures with analysis of patient tissue. This offers relevance for triaging patients who could benefit from bladder-sparing CT/RT and immunotherapy eligibility.