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The surgical resection of primary colorectal cancer is associated with an enhanced risk of liver metastases. Moreover, bacterial translocation or anastomic leakage during resection has been shown to correlate with a poor long-term surgical outcome, suggesting that bacterial products may contribute to the formation of metastases. Driven by these premises, we investigated the role of the bacterial product lipopolysaccharide (LPS) in the generation of liver metastases. Intraperitoneal injection of LPS led to enhanced tumor-cell adhesion to the rat liver as early as 1.5 h post-administration. Furthermore, a rapid loss of the expression of the tight junction protein zonula occludens-1 (ZO-1) was observed, suggesting that LPS disrupts the integrity of the microvasculature. LPS addition to endothelial-macrophage co-cultures damaged endothelial monolayers and caused the formation of intercellular gaps, which was accompanied by increased tumor-cell adhesion. These results suggest that macrophages are involved in the endothelial damage resulting from exposure to LPS. Interestingly, the expression levels of of ZO-1 were not affected by LPS treatment in rats in which liver macrophages had been depleted as well as in rats that had been treated with a reactive oxygen species (ROS) scavenger. In both settings, decreased tumor-cell adhesion was observed. Taken together, our findings indicate that LPS induces ROS release by macrophages, resulting in the damage of the vascular lining of the liver and hence allowing increased tumor-cell adherence. Thus, peri-operative treatments that prevent the activation of macrophages and—as a consequence—limit endothelial damage and tumor-cell adhesion may significantly improve the long-term outcome of cancer patients undergoing surgical tumor resection.

Vaccines against tumor associated antigens represent an appealing strategy for preventing tumor recurrence. A novel immunotherapy platform is represented by a dendritic cell vaccine that originates from a human myeloid leukemia cell line, DCOne, which endogenously expresses a range of leukemia associated antigens, including PRAME and WT-1, and can be differentiated into mature dendritic cells (DCs). Mature DC derived from DCOne are being developed to replace patient-derived DC vaccines. The first indication in which vaccination with mature DCs derived from DCOne has been tested clinically is Acute Myeloid Leukemia (AML) because of the high unmet medical need and substantial evidence that AML is a suitable target for immunotherapy. A Phase I/IIa study enrolled 12 AML patients (age range 58-71) who were either in CR1/CR2 (n=5) or had smoldering disease (n=7). Patients had received all available standard care, were at high risk of relapse and ineligible for all available post-remission therapies, including allogeneic stem cell transplantation. Patients were selected for the study because they had an estimated life expectancy of 3-6 months.

van Wetering: DCPrime: Employment. Kaur Singh:DCPrime: Employment. Hall:DCPrime: Consultancy. Kruisbeek:DCPrime: Employment.