Antitumoral immunity induced by gel ethanol ablation to treat unresectable colorectal cancer metastases in the liver

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. A quarter of CRC patients develop liver metastases. Treatment options for liver metastases include surgically removing the tumors or undergoing liver transplantation; however, many patients are ineligible for these treatments due to severe extrahepatic disease or lack of suitable donors. Radiofrequency ablation offers an alternative local treatment modality for resolving CRC liver metastases and is known to generate antitumoral effects to stunt contralateral tumor growth. However, radiofrequency ablation is not suitable for tumors situated near critical structures or large blood vessels. Ethanol ablation is an alternative treatment option where pure ethanol is directly injected into tumors to induce necrosis and is unhindered by the drawbacks from radiofrequency ablation. The addition of ethyl cellulose with ethanol (EC-ethanol) enhances its retention within tissue and subsequently improves tumor ablative efficacy. However, the antitumoral response following EC-ethanol ablation in CRC tumors is poorly understood. Thus, we utilized a CRC murine model to investigate the immune effects following EC-ethanol treatment. Studies in the single flank model demonstrated up to a 27-fold increase in IL-6 and KC/GRO pro-inflammatory cytokines within 6 hours post-treatment compared to sham treatments, along with a 4-fold increase in target-tissue necrosis and increased cytotoxic T-cells within the vicinity of the ablation zone over 7 days. Studies in the bilateral flank tumor model demonstrated that EC-ethanol ablation on the primary tumor resulted in a 1.6-fold increase in cytotoxic T-cells within the contralateral tumor after 7 days compared to the sham control group. Combining EC-ethanol treatment with radiofrequency ablation resulted in a more pronounced, 2-fold increase in cytotoxic T-cells within the contralateral tumor. Altogether, these results suggest that EC-ethanol potentiates antitumoral effects in CRC tumors and is a strong therapeutic candidate for treating CRC patients worldwide.