Regulation of macrophage-mediated antigen processing and immune suppression by Cathepsin S in glioblastoma

About the Project

Glioblastoma is the most deadly and common adult primary brain tumour. It has dismal prognosis (12-18 months survival) and standard of care treatment for patients has remained unchanged for decades, with almost 100% of patients demonstrating disease relapse. Furthermore, it is the biggest cancer-killer of the under-40s. There is an urgent need to develop new therapies for patients and recent work has highlighted that immunotherapies hold great promise in glioblastoma. However, glioblastoma has a highly immune-suppressive tumour microenvironment that limits the efficacy of existing immunotherapies.

Cathepsin S (CTSS) is a lysosomal cysteine protease which is predominantly expressed in antigen-presenting cells such as macrophages, microglia and dendritic cells. Its main role is in major histocompatibility complex (MHC) Class II antigen processing to enable peptide loading and presentation to CD4⁺ T helper cells. In glioblastoma, elevated CTSS expression correlates with tumour grade and poorer patient survival. Importantly, CTSS is increasingly recognised as a regulator of tumour immunity. Thus, this project will examine the role of CTSS in macrophage-mediated antigen processing and immune suppression in glioblastoma. We will assess how CTSS modulation impacts macrophage activity, T cell responses and immunotherapy efficacy using in vivo models, co-culture systems, and advanced immunophenotyping approaches.