Experimentally induced liver metastases from colorectal cancer can be prevented by mononuclear phagocyte-mediated monoclonal antibody therapy

Background & Aims

Development of liver metastases is a frequent complication in patients with colorectal cancer (CRC), even after successful resection of the primary tumor. As such, post-operative adjuvant therapies that aim to eliminate residual disease after surgery may improve patient outcome.

Methods

We used a colon carcinoma liver metastases model, in which CC531s colon carcinoma cells are injected into the portal circulation by a surgical procedure. As injected tumor cells are arrested in the liver, this model is suitable for investigating the interaction of tumor cells with the liver microenvironment. By administering tumor specific monoclonal antibodies (mAb) directly post-operatively, we were able to determine the effect of antibody therapy on eradication of arrested tumor cells and subsequent liver metastases outgrowth.

Results

We showed that post-operative treatment with tumor specific monoclonal antibodies (mAb) prevents liver metastases outgrowth. Antibody-dependent phagocytosis (ADPh) was the main mechanism involved, as enhanced uptake of tumor cells by innate mononuclear phagocytes in the liver was observed after mAb therapy. Furthermore, Kupffer cells (KC) were identified as the most prominent effector cells, as depletion of KC abolished therapeutic efficacy. This was partly compensated by monocytes when animals were treated with a high mAb dose, but monocytes were unable to phagocytose tumor cells when rats were treated with low mAb doses.

Conclusions

The finding that KC and monocytes can eliminate tumor cells through ADPh has important and promising clinical implications for designing new adjuvant therapies for patients undergoing CRC resection.

Abbreviations: ADCC, antibody dependent cellular cytotoxicity, ADPh, antibody dependent phagocytosis, CRC, colorectal cancer, FcγR, Fc gamma receptor, FCS, fetal calf serum, Ig, immunoglobulin, i.p., intraperitoneal, KC, Kupffer cell, mAb, monoclonal antibody, NK, natural killer

Keywords: Colorectal cancer, Metastasis, Phagocytosis, Kupffer cell, Macrophage, Antibody therapy, ADCC, Surgery