Dissecting the role of macrophage-derived cysteine cathepsin S in lung adenocarcinoma

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Lung cancer (LC) has a dismal 10-year survival rate (~5%) which has improved little in the last 40 years. This is caused in part by a highly complex immune micro-environment within the lung that permits tumours to escape recognition by the immune system. Once tumours evade the immune system, they often progress and metastasise to secondary sites such as the brain leading to a poorer prognosis. Kirsten Rat Sarcoma viral oncogene homolog (KRAS) is the most commonly mutated cancer-promoting gene in a particular lung cancer subtype, lung adenocarcinoma (LUAD), and it accounts for ~33% of cases. KRAS is known to significantly impact the current available treatment options, with responses often variable and unpredictable. Furthermore, KRAS is also known to change the tumour micro-environment through the production of pro-inflammatory molecules. Our previous research has shown certain immune cells, tumour associated macrophages (TAMs), are associated with an enhanced inflammatory tumour environment, and they express very high levels of a specific protein known as Cathepsin S (CatS). However, until now, there has been no known relationship between CatS and LUAD. We have evidence to suggest that CatS is highly elevated in LUAD and located in macrophages within these tumours. Therefore, in an effort to improve our understanding of the pathological processes involved in KRAS mutant LUAD development, we will investigate the mechanism(s) through which CatS contributes to LUAD tumour growth and progression. We will evaluate how CatS-expressing macrophages are involved in tumour development and advancement, and we will also analyse the potential therapeutic benefit that could be realised by blocking CatS activity in this cancer. Since elevated levels of CatS and pathogenic macrophages are common in many respiratory diseases including lung cancer, this project will have far reaching implications across the medical field, as it will lead to a better understanding in CatS functionality and in tumour associated inflammation and may aid in the development of more targeted therapies to treat LUAD (and other chronic respiratory diseases).