Cathepsin C promotes colorectal cancer metastasis by regulating immune escape through upregulating CSF

Since metastasis remains the primary reason for colorectal cancer (CRC) associated death, a better understanding of the molecular mechanism underlying CRC metastasis is urgently needed. Here, we elucidated the role of Cathepsin C (CTSC) in promoting CRC metastasis. The expression of CTSC was detected by real-time PCR and immunohistochemistry in the human CRC cohort. The metastatic capacities of CTSC-mediated metastasis were analyzed by in vivo metastasis model. Elevated CSTC expression was positively associated with tumor differentiation, tumor invasion, lymph node metastasis, and AJCC stage and indicated poor prognosis in human CRC. CTSC overexpression in CRC cells promoted myeloid -derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) recruitment by the CSF1/CSF1R axis. In contrast, the knockdown of CSF1 reduced CTSC-mediated MDSCs and TAMs infiltration and CRC metastasis. Deple-tion of either MDSCs or TAMs decreased CTSC-mediated CRC metastasis. In human CRC tissues, CTSC expression was positively associated with intratumoral MDSCs and TAMs infiltration. Furthermore, the combination of CTSC inhibitor AZD7986 and anti-PD-L1 antibody blocked CTSC-induced CRC metastasis. CTSC overexpression promoted MDSCs and TAMs infiltration by CSF1/CSF1R axis. Interruption of this oncogenic loop may provide a promising treatment strategy for inhibiting CTSC-driven CRC metastasis.

Automated summary

In this study, it was found that CTSC promotes metastasis in CRC. High CTSC expression is associated with poor prognosis and is positively correlated with tumor differentiation, invasion, lymph node metastasis, and AJCC stage in human CRC. CTSC overexpression leads to recruitment of MDSCs and TAMs through the CSF1/CSF1R axis, and inhibition of this axis reduces CTSC-mediated MDSCs and TAMs infiltration and CRC metastasis. Therefore, interrupting this oncogenic loop may be a promising treatment strategy for inhibiting CTSC-driven CRC metastasis.