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

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).

There are more than 47,000 diagnosed UK cases of lung cancer (LC) each year. Non-small cell lung cancer (NSCLC) accounts for the majority of these cases, and lung adenocarcinoma (LUAD) is the most common NSCLC sub-type (~40%).
Kirsten Rat Sarcoma viral oncogene homolog (KRAS) is commonly mutated in LUAD and oncogenic KRAS activation significantly impacts the tumour immune microenvironment (TME). Indeed, LUAD cancers are often hyper-inflamed with immune cells from the myeloid lineage the most frequently observed population.
Macrophages are a highly plastic family of immune cells and exhibit a variety of phenotypes, including an M1 phenotype which are deemed classically activated, pro-inflammatory with anti-tumour activity, while the M2 phenotype are alternatively activated, proangiogenic and immunosuppressive with pro-tumour activity. Tumour associated macrophages (TAMs), are governed by the nature of the local microenvironment. Furthermore, they make up a significant proportion of tumour-infiltrating immune cells in human and mouse LUAD, are often skewed towards this pro-tumour "M2-like" phenotype which aids in tumour progression through enhanced angiogenesis, local invasion and distant metastases.
M2-like TAMs produce elevated levels of cysteine proteases, including cathepsin S (CatS), that has previously been shown to enhance tumour growth, invasion, angiogenesis and pro-tumour inflammation. Previous studies have shown that inhibition of CatS can impede macrophage infiltration and inflammation and diminish tumour growth, limiting TME remodelling and metastases. While we have demonstrated that extracellular CatS has a potent, damaging impact in other chronic respiratory diseases, but its role in LUAD is yet to be elucidated.
Therefore, this project will uncover how CatS contributes to the varying stages in KRAS mutant LUAD tumourigenesis and how targeting CatS could improve therapeutic strategies for this poor prognostic tumour subtype.