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

肺癌（LC）的10年生存率很低（~5%），在过去的40年里几乎没有改善。这部分是由于肺内高度复杂的免疫微环境导致的，这种免疫微环境允许肿瘤逃避免疫系统的识别。一旦肿瘤逃避免疫系统，它们通常会进展并转移到继发部位，如大脑，导致预后较差。Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）是一种特殊的肺癌亚型肺腺癌（LUAD）中最常见的突变促癌基因，约占病例的33%。已知KRAS会显著影响当前可用的治疗方案，其反应通常可变且不可预测。此外，KRAS还已知通过产生促炎分子来改变肿瘤微环境。我们以前的研究表明，某些免疫细胞，肿瘤相关巨噬细胞（TAM），与增强的炎症肿瘤环境有关，它们表达非常高水平的特定蛋白质，称为组织蛋白酶S（CatS）。然而，到目前为止，CatS和LUAD之间还没有已知的关系。我们有证据表明CatS在LUAD中高度升高，并位于这些肿瘤内的巨噬细胞中。因此，为了提高我们对KRAS突变型LUAD发展所涉及的病理过程的理解，我们将研究CatS促进LUAD肿瘤生长和进展的机制。我们将评估表达CatS的巨噬细胞如何参与肿瘤的发展和进展，我们还将分析通过阻断这种癌症中的CatS活性可能实现的潜在治疗益处。由于CatS和致病性巨噬细胞的水平升高在包括肺癌在内的许多呼吸系统疾病中很常见，因此该项目将对整个医学领域产生深远的影响，因为它将导致更好地了解CatS功能和肿瘤相关炎症，并可能有助于开发更具针对性的治疗LUAD（和其他慢性呼吸系统疾病）。

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).