Cathepsin C correlates with M2 macrophage infiltration and regulates the tumor growth and metastasis in non-small cell lung cancer.

Cathepsin C (CTSC) is a cysteine protease in lysosomes that controls immunological responses. Upregulation CTSC expression was reportedly related with tumor progression and metastasis. The roles and mechanisms of CTSC in non-small cell lung cancer (NSCLC) are still unclear. Through systematic analysis, we found that the level of CTSC was higher in NSCLC and it was correlated with the overall survival (OS) of NSCLC patients. Furthermore, single-cell sequencing (scRNA-seq) analysis suggested that the vast majority of CTSC was expressed in epithelial cell, NK cell, M1 and M2 macrophages, and neutrophil. Gene set enrichment analysis (GSEA) demonstrated the involvement of CTSC in the immune responses and ssGSEA, CIBERSORT-abs, QUANTISEQ, XCELL algorithms results showed CTSC was positively associated with the M2 macrophages infiltration. Besides, CTSC was significantly co-expressed with M2 macrophage maker genes (CD68, CD163), and immune checkpoints. Then, CTSC, CD68, CD163 expression levels were detected by immunohistochemistry in our clinical NSCLC cohort. Subsequently, the regulatory roles of CTSC in the progression and metastasis of NSCLC were investigated both in vitro and in vivo. Our results indicated that knocking down CTSC in NSCLC cell lines restrained cell proliferation and migration. CTSC overexpression in NSCLC cells showed the opposite effects. Targeting CTSC may provide a promising treatment strategy for NSCLC patients.