HOXC10 Promotes Metastasis in Colorectal Cancer by Recruiting Myeloid-derived Suppressor Cells

Abstract

Background: Since metastasis is the primary cause of death in human colorectal cancer (CRC) patients, the exact mechanism underlying CRC metastasis remains unclear. Here, we provide evidence for a unique function of HomeoboxC10 (HOXC10) in driving CRC metastasis, as well as treatment options for these subpopulation patients. Methods: Immunohistochemistry detected the expression of HOXC10 in the human CRC cohort. The function of HOXC10 in CRC metastasis was investigated using the cecum orthotopic model. Results: In CRC patients, elevated expression of HOXC10 expression was linked to lymph node metastases, distant metastasis, worse tumor differentiation, higher AJCC stage, and poor prognosis. HOXC10 is also an independent predictive predictor for CRC patients (P<0.001). HOXC10 overexpression increased the metastasis ability of MC38 cells and promoted the infiltration of MDSCs by upregulating CXCL5 at the same time. The CXCR2 inhibitor can reduce the rate of metastasis in MC38 cells by reducing MDSCs infiltration. SB225002, a CXCR2 inhibitor, and anti-programmed death-ligand 1 (anti-PD-L1) can significantly prevent CRC metastasis. Conclusions: HOXC10 overexpression upregulated CXCL5, which promoted MDSCs infiltration. Interrupting this loop might be a potential therapy option for HOXC10-induced CRC metastasis.

Role of imbalanced gut microbiota in promoting CRC metastasis: from theory to clinical application

“…Both myeloid-derived suppressor cells (MDSCs) and tumour-associated macrophages (TAMs) can be recruited by F. nucleatum to suppress immunity in CRC patients [ 61 ]. Among them, MDSCs have become an important component of TME, which can significantly inhibit T cell activity, with potent immunosuppressive effects and the potential to promote CRC metastasis [ 62 , 63 ]. Additionally, macrophages have the ability to phagocytose tumour cells alive, leading to the death of tumour cells, which seems to be an important mechanism of tumour immunity [ 64 ].…”

Myeloid-Derived Suppressor Cells: Therapeutic Target for Gastrointestinal Cancers

“…In CRC and pancreatic cancer, MDSCs play an important role in enabling this process. PMN-MDSC depletion inhibits progression of CRC peritoneal disease [ 13 ], while CXCR2 inhibitor can reduce the rate of metastasis by reducing the MDSC infiltration [ 14 , 15 ]. Finally, CXCR2+ MDSCs in the premetastatic niche promote CRC tumor cell survival [ 16 ], and M-MDSCs promote the growth of CRC micro-metastases to macro-metastases [ 17 ].…”

Combined Inhibition of Indolamine-2,3-Dioxygenase 1 and C-X-C Chemokine Receptor Type 2 Exerts Antitumor Effects in a Preclinical Model of Cervical Cancer

“…Combining different immunotherapeutic agents, such as immune checkpoint inhibitors, adoptive T cell therapies, cytokines, and vaccines, can create a more comprehensive and dynamic immune response against the disease. For example, studies indicated that when used as a single agent, IDO-1 or CXCR-2 inhibitors exerted little antitumor efficacy, while combination with other therapies showed markedly enhanced antitumor effectiveness [ 32 , 33 , 34 , 35 ]. On the contrary, a phase 1 clinical study yielded inconclusive evidence concerning the potential benefits of combined therapy incorporating the IDO-1 inhibitor (navoximod) and the PD-L1 inhibitor (atezolizumab) in solid tumors, including CC [ 36 ].…”