Immunogenic cell death in cancer therapy

Abstract

Triple negative breast cancer (TNBC) is a heterogenous disease which carries a poor prognosis, with the worst outcomes in the basal-like subtype. Despite the introduction of immunotherapy in the treatment paradigm the response rates are modest, especially in advanced disease. There remains an unmet clinical need for novel treatment approaches to improve tumour-specific immune responses for disease control. Conventional cancer treatments cause cell death and the mechanism of this death can determine anti-cancer immunity. The main aim of this thesis was to understand how treatment mediated cell death could be manipulated to engage TNF-mediated death receptor signalling to promote a more immunogenic cell death in this breast cancer subtype. To understand tumour immune responses an immune-competent in vivo model was required. To this end, organoid models were derived from spontaneously forming mammary tumours in genetically engineered (GEMM) BLG-Cre;Brca1f/f;p53+/- mice. These could be reimplanted in syngeneic mice and formed organoid derived tumours that reflected the heterogeneous primary tumours with human basal-like features. To complement this model, and address the clinical validity of murine experiments, I also developed techniques to measure the modality of cell death in human TNBC Patient Derived Organoids (PDOs) from the BCN Organoid Facility. I have shown that GEMM BLG-Cre;Brca1f/f;p53+/- organoids have necroptotic machinery and that the combination of IAP antagonists and caspase inhibition can drive TNF-mediated necroptotic cell death. In immune infiltrated tumours this can enhance immune checkpoint inhibitor (ICI) responses. Furthermore, in organoid derived tumours with an increased interferon gene signature, the addition of STING agonism in vivo sensitises tumours to necroptosis. In most human TNBC models RIPK3 is absent and chemotherapy causes apoptotic cell death. Releasing the break on RIPK1, using IAP antagonists, can further drive cell death in PDOs treated with chemotherapy, PARP inhibition and novel antagonists of anti-apoptotic BH3 family proteins. Furthermore, engaging the IFN pathway can induce RIPK1 mediated death which may be more immunogenic. Overall, this work suggests that engaging RIPK1 signalling using novel drug combinations may be a promising strategy to harness the potential for therapy induced immunogenic cell death and anti-tumour immune responses.