Profiling the immune landscape of breast cancer and the identification of potential therapeutic strategies

Abstract

Breast cancer (BC) is a highly heterogeneous disease at both the molecular and immune level. Recent evidence suggests that a key factor influencing response to treatment is the state of immune activation, with immune hot tumours (high levels of tumour infiltrating lymphocytes) associated with improved outcome.

 Stimulator of Interferon Genes (STING), is an immune modulator implicated in sensing double-stranded DNA in the cytosol. It is therefore reasonable to assume STING activation in cancer. However, as not all cancers are associated with TILs, STING activity may be suppressed or hindered by the action of immunosuppressive mechanisms.

 Using the digital image analysis tool QuPath, a multitude of well accepted immune biomarkers were quantified by IHC and correlated with matched clinical outcome data, as well as STING activity scores, generated from the application of a novel algorithm for perinuclear STING quantification. High perinuclear STING expression was associated with improved outcome in high-risk ER+ BC, treated with chemotherapy, suggesting a proportion of patients may benefit STING activation. However, successful systemic activation of STING has been difficult to date, as the natural ligand, cGAMP is rapidly degraded in the bloodstream. Therefore, a novel delivery system, capable of delivering cGAMP to the target tumour site is required. Using the RALA peptide based delivery system, two novel methods to potentially activate STING signaling have been proposed with the unique advantage of suitability for in vivo application and translatability. The preliminary data presented in this study warrants further assessment of RALA/siRNA and RALA/cGAMP nanoparticles in a syngeneic model.

 To conclude, a population of BC patients with low levels of STING activity and who do not benefit from current standard of care treatments have been identified. These patients may benefit from STING activation however, given the upregulation of immune checkpoints, combination treatment with immune checkpoint inhibitors may be required. 

Thesis embargoed until 31 July 2029.

Date of Award	Jul 2024
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Northern Ireland Department for the Economy
Supervisor	Niamh Buckley (Supervisor), Helen McCarthy (Supervisor) & Eileen Parkes (Supervisor)